ANGPT1 functions as a TIE2 agonist, which induces receptor phosphorylation and activates downstream signalling pathways. ANGPT1-induced TIE2 activation results in endothelial cell survival signals and the maintenance of the endothelial barrier and quiescent vasculature.
ANGPT2 normally functions as an ANGPT1antagonist and increases vascular permeability, destabilizes quiescent vasculature and primes the endothelial bed for angiogenesis. When functioning as an ANGPT1n antagonist, ANGPT2 promotes the dissociation of pericytes from pre-existing vessels and increases vascular permeability, which facilitates the infiltration of proteases, cytokines and angiogenic myeloid cells — which prime the vasculature for a robust angiogenic response in the presence of growth factors such as VEGFA.
Vascular endothelial (VE)-cadherin is specifically expressed in the endothelium. Previous work showed that VE-cadherin associates to VEGF-R2 and modulate its signaling pathways. In the absence of VE-cadherin, VEGF-R2 is heavily tyrosinephosphorylated and promotes endothelial cell growth in anuncontrolled way, accompanied by an increase in cell apoptosis.
CXCL5, a member of the CXC chemokine family, has been shown to be involved in angiogenesis, tumor growth, and metastasis. Overexpression of CXCL5 is associated with poor survival in patients with pancreatic cancer. Overexpression of CXCL5 is significantly correlated with poorer tumor differentiation, advanced clinical stage, and shorter patient survival.
IL8 is a proinflammatory CXC chemokine associated with the promotion of neutrophil chemotaxis and degranulation. As a consequence of the diversity of effectors and downstream targets, IL-8 signaling promotes angiogenic responses in endothelial cells, increases proliferation and survival of endothelial and cancer cells, and potentiates the migration of cancer cells, endothelial cells, and infiltrating neutrophils at the tumor site. IL-8 signaling has been implicated in regulating the transcriptional activity of the androgen receptor, underpinning the transition to an androgen-independent proliferation of prostate cancer cells. In addition, stress and drug-induced IL-8 signaling has been shown to confer chemotherapeutic resistance in cancer cells.
CXC-chemokine receptor type 2 (CXCR2) was reported to play critical roles in angiogenesis, tumorigenesis, and metastasis of several cancers such as colon cancer, melanoma, lung cancer, and so on.
VEGF receptors, Flt-1, KDR, and Flt-4 form a subfamily within the platelet-derived growth factor receptor class.
VEGF receptors, Flt-1, KDR, and Flt-4 form a subfamily within the platelet-derived growth factor receptor class. Strong KDR expression was associated with histological transformation of FL, and both VEGF and VEGF-C expression were upregulated in biopsies taken at the time of transformation as compared to the primary FL biopsies, suggesting a possible role of the angiogenic molecules in the progression from FL to DLBCL.
An increasing number of studies indicate a multi-faceted role for PDGFC: it is involved in angiogenesis, fibroblast recruitment and the stimulation of tumour growth through an autocrine mechanism. A recent study also reports that, similar to other PDGF family members, PDGFC might recruit pericytes, resulting in the formation of more mature, stabilized blood vessels that are refractory to anti-VEGF treatment.
PIGF expression, unlike that of VEGF, is undetectable in most organs in healthy conditions, but is highly upregulated in tumor conditions, contributing to the angiogenic and inflammatory switch. In tumors, PlGF is not only produced by malignant cells, but also by endothelial cells, smooth-muscle cells, pericytes, cancer-associated fibroblasts, tumor-associated macrophages, and various other inflammatory cells in tumor stroma. PlGF induces various biological effects by affecting a wide range of different cell types. PlGF can stimulate vessel growth and maturation directly by affecting endothelial and mural cells, and indirectly by recruiting pro-angiogenic cell types. For example, PlGF stimulates the growth, migration and survival of endothelial cells, increases the proliferations of fibroblasts and smooth-muscle cells, induces vasodilatation, and stimulates collateral vessel growth. It also promotes the recruitment and maturation of angiogenesis-competent myeloid progenitors to growing sprouts and collateral vessels. In addition, PlGF activates and attracts macrophages that release angiogenic and lymphangiogenic molecules, and inhibits the differentiation of dendritic cells.
ANGPT1 functions as a TIE2 receptor agonist, and ANGPT2 normally functions as an ANGPT1 antagonist. TIE2 is predominantly expressed on endothelial cells and binds all the known ANGPT ligands.
VEGF is one of the most potent angiogenic stimulants with several biologic effects, including the maintenance and the survival of newly formed blood vessels.
This growth factor is able to directly stimulate endothelial-cell growth and migration by increasing the secretion of proteinases in vitro and to promote capillary tube formation in Matrigel in vivo. In many cases, VEGFB levels are increased in malignant tissues, such as in ovarian, colorectal, renal cell and prostate cancer.
VEGF-C and VEGF-D are able to activate both KDR and VEGFR-3 (Flt-4) and have a dual role as an angiogenic and lymphangiogenic growth factor.
VWF 伪v尾3, which is expressed on EC and is the best characterised endothelial receptor for VWF, has been shown to play a crucial role in angiogenesis and is a therapeutic target for cancer. VWF is produced by endothelial cells and megakaryocytes. In recent years, it has become evident that VWF plays multiple roles in the vasculature. VWF has been shown to control smooth muscle cell proliferation, vascular inflammation, cell death and tumour metastasis. VWF was found to regulate two pathways, possibly linked, which may be controlling angiogenesis: an extracellular pathway involving integrin 伪v尾3 and an intracellular pathway involving Ang-2 storage in WPB. Besides Ang-2, VWF interacts with or regulates the storage of several proteins which have been implicated in the control of angiogenesis, including interleukin-8, galectin-1 and galectin-3, connective tissue growth factor59 and insulin-like growth factor binding protein-7. These studies suggest that VWF controls stability and quiescence through an intracellular pathway, by directing the formation of WPB and hence the storage of Ang-2 (and possibly other angiogenic regulators), and extracellular pathway, by stabilizing 伪v尾3 on the cell surface and regulating its levels and activity.
The presence of CD8+ T cells in the melanoma microenvironment is associ颅ated with local production of CCL2, CCL3, CCL4, CCL5, CXCL9 and CXCL10.
IFN伪 and IFN尾 have important functions in homeostasis and antitumour immunity.
IFN尾 has pleotropic effects, including antiviral, antitumor, and anti-inflammation. IFN尾 suppresses inflammatory responses in MS patients by four major mechanisms, including blocking T cell activation, controlling pro- and anti-inflammatory cytokine secretion, preventing activated immune cell migration through BBB, and inducing repair activity of damaged nerve cells by differentiating neural stem cells into oligodendrocytes.
IL-21 is produced by a variety of activated CD4+ T cells including TH1 and TH17 cells, natural killer T (NKT) cells and follicular helper T cells. IL-21 exerts potent antitumor effects due to its ability to induce and expand cytotoxic CD8+ T cells, NK cells and NKT cells, as well as to its capacity to suppress FOXP3 expression and the expansion of regulatory T cells
Tumor necrosis factor alpha (TNF-alpha), isolated 30 years ago, is a multifunctional cytokine playing a key role in apoptosis and cell survival as well as in inflammation and immunity. If expressed chronically, contributes to the chronic inflammation (promotes TGF-beta expression, Treg expansion, EMT).
TRAIL, a member of the TNF family, induces apoptosis in a variety of transformed cells following ligation to TRAIL-Receptor-1/DR4 and -2/DR5. TRAIL can induce apoptosis in transformed cells of diverse origin with little or no effects on normal cells and exhibits antitumor activity in several xenograft studies without systemic toxicity.
Blk is exclusively expressed in B cells and thymocytes but not in mature T cells. Besides a role of Blk in B-cell receptor (BCR) signaling and B-cell development, the cellular functions of Blk are poorly defined.
CD19 is critically involved in establishing intrinsic B cell signaling thresholds through modulating both B cell receptor-dependent and independent signaling. CD19 functions as the dominant signaling component of a multimolecular complex on the surface of mature B cells.
CD22 is expressed in mature B cells, but not in their precursor or memory B cells. It is strongly expressed in follicular, mantle and marginal-zone B cells, but is weakly present in germinal B cells, thus indicting its potential therapeutic target for B-NHL. The function of CD22 has not been entirely clarified; it acts as a homing receptor for recirculating B cells through the affinity of the lectin-like domains for 2,6-linked sialic acid-bearing glycans and as a B-cell antigen receptor (BCR) down-modulating co-receptor.
Among the different B-cell markers, CD79a has the highest linage-specificity for B-cell differentiation, with a specificity of 88% and a sensitivity of 100%. It is a cell-surface molecule having a cytoplasmic domain that is associated physically with membrane immunoglobulins. CD79a is needed for B-cell differentiation and is expressed in the early and late stages of B-cell development.
The BCR consists of the antigen-binding immunoglobulin heavy (IgH) and light (IgL) chains coupled to a heterodimer of the signaling subunits CD79A (Ig伪) and CD79B (Ig尾).
The complement receptor type 2 (CR2, CD21) binds to fragments of complement C3 (C3d, C3dg and iC3b), and together with CD19 and CD81 forms a co鈥恟eceptor to the B cell receptor (BCR). The binding of complement鈥恡agged antigens to the BCR and CD21 results in co鈥恖igation, which amplifies signals transduced through the BCR and thus lowers the B cell activation threshold.
Fc receptor-like 5 (FcRL5/FcRH5/IRTA2/CD307) is a surface protein expressed selectively on B cells and plasma cells.
The cell surface protein CD20 is a 33-kDa protein, which is expressed almost exclusively on B cells from beyond pre-B-cell stage but is lost as postgerminal cells differentiate to become plasma cells. The function of CD20 is unknown, but suggested to contribute to ion channel formation in all B cells (malignant and nonmalignant).
BSAP/PAX-5 is thought to repress Ig heavy chain transcription in immature and mature B cells by inhibiting the activity of the Ig heavy chain 3′ α chain enhancer in these cells.
STAP1 is a relatively unknown protein, consisting out of Peckstrin homology (PH) domains and unique Src homology 2 (SH2) domains, suggesting that STAP1 recruits signaling proteins to receptor tyrosine kinases. STAP1 is reported to be a docking protein downstream of Tec protein tyrosine kinase (TEC), which is involved in BCR signaling. In addition, reports show enriched expression in hematopoietic stem cells and a potential role of STAP1 in microglia activation has been suggested.
BAFF can bind to three receptors, B-cell maturation antigen (BCMA), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and BAFF-receptor (BAFF-R) (also known as BR3). BCMA and TACI also bind to another TNF family member, a proliferation-inducing ligand. TACI is considered to be a negative regulator of B-cell homeostasis.
This molecule was first identified as one of three receptors that bind the B-cell survival factor of the TNF-family or BAFF (also known as BLyS, TALL-1, THANK and zTNF4). BAFF-R regulates the survival of resting B cells, in part through protecting cells from apoptosis.
A proliferation-inducing ligand (APRIL), as well as its receptors transmembrane activator and calcium-modulating cyclophilin ligand (CAML) interactor (TACI) and B-cell maturation antigen (BCMA), has been shown to be important in B-cell biology.
Myofibroblasts acquire contractile stress fibers, de novo express 伪-smooth muscle actin (伪-SMA) and the ED-A splice variant of fibronectin, and form cell-cell contacts through gap junctions.
Endosialin (Tem1) is a marker of tumor-associated myofibroblasts and tumor vessel-associated mural cells.
The 伪1 chain of type XI collagen (COL11A1) has been shown to be overexpressed in cancer-associated stromal fibroblasts.
Many of the constituents of the ECM and basement membranes — such as type I, type III, type IV and type V collagens, many different laminins and fibronectin — are produced by activated fibroblasts or myofibroblasts.
Many of the constituents of the ECM and basement membranes — such as type I, type III, type IV and type V collagens, many different laminins and fibronectin — are produced by activated fibroblasts or myofibroblasts.
Many of the constituents of the ECM and basement membranes — such as type I, type III, type IV and type V collagens, many different laminins and fibronectin — are produced by activated fibroblasts or myofibroblasts.
Type VI collagen (COL6) forms a microfibrillar network that is often associated with type I collagen fibrils and may bind them together to form thicker collagen fibers. The COL6 protein is comprised of three different alpha chains and the major form is made up of 伪1, 伪2, 伪3 chains.
Type VI collagen (COL6) forms a microfibrillar network that is often associated with type I collagen fibrils and may bind them together to form thicker collagen fibers. The COL6 protein is comprised of three different alpha chains and the major form is made up of 伪1, 伪2, 伪3 chains.
In current study, we chose COL6A3, an ECM protein, for further analysis. By TMA-IHC analysis, we further revealed that COL6A3 protein was significantly upregulated in the stromal cells of CRC tissues comparing with the normal counterparts. Interestingly, the upregulation of COL6A3 in cancer stroma predicted poor outcome of CRC patients, as revealed by the Kaplan-Meier survival analysis.
CXCL12, also known as SDF1a, binds to its cognate receptor, CXCR4. Previous studies showed that CAFs secrete CXCL12, stimulate CXCL12/CXCR4 signaling and promote tumor growth and angiogenesis in breast cancer and non-small cell lung cancer.
FAP is a membrane-bound serine protease of the prolyl oligopeptidase family with unique post-prolyl endopeptidase activity. The identification of fibroblast activation protein 伪 (FAP) as a target selectively expressed on fibroblasts within the tumor stroma or on carcinoma-associated fibroblasts led to intensive efforts to exploit this novel cellular target for clinical benefit.
In contrast to normal fibroblasts, cancer-associated fibroblasts (CAFs) enhance tumor growth and metastasis through the production of growth factors and ECM proteins and modulating immune polarization. They also have different gene signatures related to paracrine signaling, transcriptional regulation, extracellular matrix, cell-cell interaction and cell adhesion/migration such as wnt1 inducible signaling pathway protein 1 (WISP1), kruppel like factor 4 (KLF4), TGF尾2, fibulin1 (FBLN1), plasminogen activator inhibitor 2 (PAI2), and tissue plasminogen activator (PLAT).
Fibroblast surface-associated FGF-2 promotes contact-dependent colorectal cancer cell migration and invasion.
In particular, miR-200 s and their targets all contributed to CAF-associated ECM remodeling through two key ECM remodeling proteins, fibronectin (FN) and lysyl oxidase, further fueling cancer cell invasion and metastasis.
LRP1 is a large transmembrane receptor that is abundantly produced by fibroblasts. LRP1 has been found in a wide range of human malignancies.
Lumican is an extracellular protein belonging to the family of small leucine-rich repeat proteoglycans (SLRPs). Cancer-associated fibroblast-derived Lumican promotes gastric cancer progression via the integrin 尾1-FAK signaling pathway.
Specifically, MFAP5, a protein component of extracellular microfibrils, was enriched in CAF secretomes. Using in vitro assays, we demonstrated that MFAP5 activated OTSCC cell growth and migration via activation of MAPK and AKT pathways.
The data indicate both upregulation and activation of matrix metalloproteinases (MMPs)-1, -2, and -3 are characteristic of the cancer-associated myofibroblast (CAM) secretome.
The data indicate both upregulation and activation of matrix metalloproteinases (MMPs)-1, -2, and -3 are characteristic of the cancer-associated myofibroblast (CAM) secretome.
Platelet-derived growth factor is a major mitogen for several cell types, including connective tissue cells, that is activated by binding to two protein tyrosine kinase receptors (PDGFR伪 and PDGFR尾). The results from our study revealed that higher grade PT with more active fibroblasts showed higher expression of PDGFR伪 and 尾, suggesting that fibroblasts with a CAF phenotype are associated with PT progression.
Platelet-derived growth factor is a major mitogen for several cell types, including connective tissue cells, that is activated by binding to two protein tyrosine kinase receptors (PDGFR伪 and PDGFR尾). The results from our study revealed that higher grade PT with more active fibroblasts showed higher expression of PDGFR伪 and 尾, suggesting that fibroblasts with a CAF phenotype are associated with PT progression.
BTLA was first identified as an inhibitory receptor on T cells. Subsequently, herpesvirus entry mediator (HVEM; also known as TNFRSF14) — which is expressed on certain tumour cell types (for example, melanoma) as well as on tumour-associated endothelial cells — was shown to be the BTLA ligand. BTLA may also be a relevant inhibitory receptor for T cells in the tumour microenvironment. Dual blockade of BTLA and PD1 clearly enhances antitumour immunity.
Interaction between the Programmed Death Ligand 1 (PD-L1) on the surface of tumor cells with the Programmed Death-1 (PD-1) receptor on cytotoxic T lymphocytes leads to inactivation of these immune effectors and, consequently, immune escape. Here we show that the PD-1/PD-L1 axis also leads to tumor cell resistance to conventional chemotherapeutic agents.
CTLA4, the first immunecheckpoint receptor to be clinically targeted, is expressed exclusively on T cells where it primarily regulates the amplitude of the early stages of T cell activation. Primarily, CTLA4 counteracts the activity of the T cell co-stimulatory receptor, CD28. CD28 does not affect T cell activation unless the TCR is first engaged by cognate antigen. Once antigen recognition occurs, CD28 signalling strongly amplifies TCR signalling to activate T cells. CD28 and CTLA4 share identical ligands: CD80 (also known as B7.1) and CD86 (also known as B7.2). Although the exact mechanisms of CTLA4 action are under considerable debate, because CTLA4 has a much higher overall affinity for both ligands, it has been proposed that its expression on the surface of T cells dampens the activation of T cells by outcompeting CD28 in binding CD80 and CD86, as well as actively delivering inhibitory signals to the T cells.
TIM3, the ligand of which is galectin 9 (a galectin that is upregulated in various types of cancer, including breast cancers) inhibits T helper 1 (TH1) cell responses. TIM3 has also been reported to be co-expressed with PD1 on tumour-specific CD8+ T cells, and dual blockade of both molecules significantly enhances the in vitro proliferation and cytokine production of human T cells when stimulated by the cancer鈥搕estes antigen, NY-ESO-1. In animal models, coordinate blockade of PD1 and TIM3 was reported to enhance antitumour immune responses and tumour rejection in circumstances in which only modest effects from blockade of each individual molecule were observed.
LAG-3 (CD223) is a member of the immunoglobulin superfamily and is expressed on a variety of cell types including T cells, NK cells, B cells and dendritic cells. LAG-3 is generally absent on resting T cells and is upregulated on activated T cells. By interacting with its ligand, MHC class II, LAG-3 plays a negative regulatory role and suppresses T cell function.
The major role of PD1 is to limit the activity of T cells in peripheral tissues at the time of an inflammatory response to infection and to limit autoimmunity. When engaged by one of its ligands, PD1 inhibits kinases that are involved in T cell activation through the phosphatase SHP250, although additional signalling pathways are also probably induced. Also, because PD1 engagement inhibits the TCR ‘stop signal’, this pathway could modify the duration of T cell–APC or T cell–target cell contact.
PD1 only inhibits lymphocyte function when it is engaged by its ligands, PDL1 and PDL2. PDL2 has also been reported to be upregulated in various tumours.
This approach identified TIGIT as the most frequently expressed co-inhibitory receptor in FL T cells, and the expression was associated with T-cell dysfunction. Taken together, our data suggest TIGIT as a promising new target for immune checkpoint blockade in FL.
The frequent observation of increased expression of intratumoral VISTA+ lymphocytes during acquired resistance to immune checkpoint inhibitor therapy suggests that this is probably an important mechanism of resistance.
In normal tissues, signaling through CD40 has been implicated in enhanced antigen presentation function and cytokine release. CD40 ligand (CD40L), also known as CD154, functions as the natural ligand for CD40. It is expressed primarily on the surface of activated T lymphocytes but has also been found on activated platelets. CD40L is a major component of T-cell help for B cells in antibody isotype switching and in the formation of memory B cells and germinal centers.
CD27, a member of the tumor necrosis factor receptor superfamily, acts as a potent costimulatory molecule that, unlike other related family members, is expressed constitutively on unstimulated T lymphocytes. CD70, the ligand for CD27, is transiently expressed on antigen-presenting cells. CD27-CD70 mediated costimulation — concomitant with antigen-specific T-cell receptor (TCR) stimulation — results in T-cell activation, proliferation, survival, and maturation of effector capacity and T-cell memory. CD27-CD70 interactions also promote B-cell proliferation, generation of plasma cells, production of immunoglobulin and B-cell memory, and induction of the cytolytic activity of natural killer (NK) cells.
The B7-related molecules CD80 and CD86 are expressed on antigen-presenting cells, bind the homologous T cell receptors CD28 and CTLA-4, and trigger costimulatory signals important for optimal T cell activation. Despite limited sequence identity, CD80 and CD86 share similar overall receptor binding properties and effector functions.
Human CD83 is a marker molecule for mature dendritic cells (DC) and is also expressed on activated B and T cells. In conclusion, we demonstrate that CD83 expression on T cells and DC modulates the immune response by activating DC and by delivering costimulatory signals for the stimulation of naive and memory T cells, respectively.
The B7-related molecules CD80 and CD86 are expressed on antigen-presenting cells, bind the homologous T cell receptors CD28 and CTLA-4, and trigger costimulatory signals important for optimal T cell activation. Despite limited sequence identity, CD80 and CD86 share similar overall receptor binding properties and effector functions.
ICOS binds to the related molecule B7H (also known as B7RP1, LICOS or GL50). Ligation of ICOS by B7H might occur in the absence of CD80 and CD86, and so provide the minimal CD28-like signals that are required for costimulation. This would allow the clonal expansion of TH2 cells without concurrent activation of TH1 cells through CD28 co-stimulation. ICOS might also operate together with CD28 to alter the threshold of signalling. Conversely, although ICOS and CD28 enhance the production of interferon-纬 (IFN-纬), IL-4 and IL-10, ICOS only marginally induces IL-2 production.
OX40 is a member of the tumor necrosis factor receptor superfamily and interactions between OX40 and OX40L act as costimulatory signals. We and others have extensively studied the functions of OX40 and OX40L in the immune system, including the generation of memory T cells and the stimulation of CD4 T cells, CD8 T cells, and natural killer T cells. Triggering OX40 signaling has been demonstrated in various mouse tumor models as a potential antitumor therapy and its translation to clinical trials is under investigation.
CD137 (4-1BB, TNFRSF9) glycoprotein is a member of the tumor necrosis factor receptor superfamily and binds to a high-affinity ligand (CD137L, 4-1BBL, TNFSF9) expressed on antigen-presenting cells such as dendritic cells, macrophages, and activated B cells. CD137 is shown to be an important costimulatory molecule for T-cell activation. Engagement of CD137 on T cells by natural ligand or agonist monoclonal antibody (mAb) enhances T-cell proliferation and provides protection to CD8 T cells from activation-induced cell death through nuclear factor 魏B鈥搈ediated activation and up-regulation of the antiapoptotic Bcl-2 family members Bcl-xL and Bfl-1. Stimulation of CD137 could also lead to activation of dendritic cells, NK cells, and macrophages in vitro.
CD27, a member of the tumor necrosis factor receptor superfamily, acts as a potent costimulatory molecule that, unlike other related family members, is expressed constitutively on unstimulated T lymphocytes. CD70, the ligand for CD27, is transiently expressed on antigen-presenting cells. CD27-CD70 mediated costimulation — concomitant with antigen-specific T-cell receptor (TCR) stimulation — results in T-cell activation, proliferation, survival, and maturation of effector capacity and T-cell memory. CD27-CD70 interactions also promote B-cell proliferation, generation of plasma cells, production of immunoglobulin and B-cell memory, and induction of the cytolytic activity of natural killer (NK) cells.
The key role of CD28 in promoting full activation of naive T cells is illustrated by its direct effects on gene activation, cell cycle and survival, and in inducing the expression of a second wave of membrane receptors by activated T cells and by CD28-mediated in direct (or long-range) effects on clonal expansion and T-cell differentiation.
In normal tissues, signaling through CD40 has been implicated in enhanced antigen presentation function and cytokine release. In B cells, CD40 cross-linking results in immunoglobulin class switching and growth stimulation. CD40 has been demonstrated on all normal B-lymphocytes, as well as populations of epithelial cells, CD341 hematopoietic progenitor cells, monocytes, dendritic cells, endothelial cells, and fibroblasts.
ICOS is a T-cell coregulatory receptor that provides a costimulatory signal to T cells during antigen-mediated activation. Taken together, our results showed that ICOS signaling during antitumor responses acts on both Teff and Treg cells, which have opposing roles in promoting immune activation.
OX40 is a potent co-stimulatory receptor that can potentiate T cell receptor signaling on the surface of T lymphocytes, leading to their activation by a specifically recognized antigen. In particular, OX40 engagement by ligands present on dendritic cells dramatically increases the proliferation, effector function and survival of T cells.
CD137 (4-1BB, TNFRSF9) glycoprotein is a member of the tumor necrosis factor receptor superfamily and binds to a high-affinity ligand (CD137L, 4-1BBL, TNFSF9) expressed on antigen-presenting cells such as dendritic cells, macrophages, and activated B cells. CD137 is shown to be an important costimulatory molecule for T-cell activation. Engagement of CD137 on T cells by natural ligand or agonist monoclonal antibody (mAb) enhances T-cell proliferation and provides protection to CD8 T cells from activation-induced cell death through nuclear factor 魏B鈥搈ediated activation and up-regulation of the antiapoptotic Bcl-2 family members Bcl-xL and Bfl-1. Stimulation of CD137 could also lead to activation of dendritic cells, NK cells, and macrophages in vitro.
Because it seemed likely that the protein array approach might not be sensitive enough to detect chemokines in low abundance, real-time RT-PCR was done for expression of CXCL9/Mig, CXCL10/IP-10, and CCL3/MIP-l伪. Each of these also was confirmed to be expressed at higher levels in the T-cell-containing tumors.
Quantitatively, CCL4 expression was significantly greater in the T-cell-containing tumors (mean intensity 37 卤 25 compared with 0 卤 0; P = 0.005) as was CCL5 (mean intensity, 59 卤 27 versus 10 卤 10; P = 0.003).
Quantitatively, CCL4 expression was significantly greater in the T-cell-containing tumors (mean intensity 37 卤 25 compared with 0 卤 0; P = 0.005) as was CCL5 (mean intensity, 59 卤 27 versus 10 卤 10; P = 0.003).
Fractalkine (FKN) is a unique CX3C chemokine (CX3CL1) known to induce both adhesion and migration of leukocytes mediated by a membrane-bound and a soluble form, respectively. Its function is mediated through CX3C receptor (CX3CR), which is expressed by T(H)1 immune cells including T cells and natural killer (NK) cells.
Fractalkine (FKN) is a unique CX3C chemokine (CX3CL1) known to induce both adhesion and migration of leukocytes mediated by a membrane-bound and a soluble form, respectively. Its function is mediated through CX3C receptor (CX3CR), which is expressed by T(H)1 immune cells including T cells and natural killer (NK) cells.
The two chemokines and CXCR3 receptor ligands CXCL9 and CXCL10 mediate the recruitment of tumour-suppressive CXCR3+ T cells and natural killer (NK) cells into solid cancers. Correspondingly, a high intratumoral concentration of these chemokines is associated with a higher lymphocytic infiltrate and an improved survival in several malignancies.
However, CXCL11 shows higher affinity for CXCR3 than either CXCL9 or CXCL10, and consequently is a more potent activator of the receptor. The two functions of CXCL11, inhibition of angiogenesis and attraction of tumor-specific CTL (this study) may act synergistically and lead to tumor regression.
The two chemokines and CXCR3 receptor ligands CXCL9 and CXCL10 mediate the recruitment of tumour-suppressive CXCR3+ T cells and natural killer (NK) cells into solid cancers. Correspondingly, a high intratumoral concentration of these chemokines is associated with a higher lymphocytic infiltrate and an improved survival in several malignancies.
The two chemokines and CXCR3 receptor ligands CXCL9 and CXCL10 mediate the recruitment of tumour-suppressive CXCR3+ T cells and natural killer (NK) cells into solid cancers. Correspondingly, a high intratumoral concentration of these chemokines is associated with a higher lymphocytic infiltrate and an improved survival in several malignancies.
The CD8伪尾 heterodimer functions as a coreceptor with the TCR, influencing the outcome of CD8+ T cell responses to pathogen-infected and tumor cells.
The CD8伪尾 heterodimer functions as a coreceptor with the TCR, influencing the outcome of CD8+ T cell responses to pathogen-infected and tumor cells.
Eomesodermin (EOMES) is an important transcription factor controlling the function of effector CD8+ T cells. The expression of EOMES in CD8+ T cells may reflect a critical basal level of immune competence of the melanoma patient. CD8+ T cells play a vital role in the immune response to melanoma, and their baseline level of activation and function may be a sine qua non for the therapeutic effect of ipilimumab.
In addition to the perforin/granzyme pathway and some indirect mechanisms involving cytokines such as tumor necrosis factor-伪 (TNF伪) and interferon-纬, CD95/CD95L is a direct major system that both CTLs as well as CD4+ cytolytic effector T cells use to eliminate neoplastically transformed cells.
Granulysin was first known as an intracellular cytolytic molecule within granules of CTLs and NK cells. Originally, the cytolytic function of granulysin was demonstrated in cells infected with intracellular organisms such as Mycobacterium tuberculosis; this molecule was later shown to also be effective against tumor cells.
CTL/NK cells recognize and kill infected or abberant target cells by two major pathways: either through introduction of a battery of proteases – called granzymes – to the target cell cytosol, or through TNF superfamily-dependent killing. Granzyme A promotes cell death by targeting the nucleus and also mediates the release of mature IL-1β.
CTL/NK cells recognize and kill infected or abberant target cells by two major pathways: either through introduction of a battery of proteases – called granzymes – to the target cell cytosol, or through TNF superfamily-dependent killing. On entry into the target cell cytosol, granzyme B promotes apoptosis through two main pathways, either through BID-dependent mitochondrial permeabilization or through direct caspase processing and activation.
As a member of the granzyme family, GZMK (previously known as tryptase-2) is implicated in one of the mechanisms used by cytotoxic T lymphocytes and NK cells to induce the apoptosis of tumor cells.
IFN-纬 signaling in the tumor cell plays a role in enhancing tumor immunogenicity, promoting the infiltration of mononuclear cells into tumor tissue, and inhibiting tumor angiogenesis. The main cellular producers of IFN-纬 are Type 1 CD8+ T cells, NK cells, and Th1 CD4+ T cells.
Loss of perforin leads to a complete failure of effector cells to lyse targets in vitro.
T-bet is a hallmark transcription factor that is essential for differentiation and function of Th1 cells, CD8+ T cells, 纬未 T cells and NK cells.
ZAP-70 (味-associated protein of 70 kDa) is a tyrosine kinase of the Syk family that plays a critical role in triggering the signalling cascade in response to T-cell receptor stimulation. This signalling pathway leads to the activation of different effector enzymes that ultimately will activate different transcription factors enhancing gene expression in antigen-stimulated T- and NK-cells.
VE-cadherin is an adhesive protein, known to be expressed exclusively by endothelial cells, and belongs to the cadherin family of transmembrane proteins promoting homotypic cell-to-cell interaction.
Tumor endothelial markers (TEMs) that are highly expressed in human tumor vasculature compared with vasculature in normal tissue hold clear therapeutic potential. We report that the C-type lectin CLEC14A is a novel TEM. Immunohistochemical and immunofluorescence staining of tissue arrays has shown that CLEC14A is strongly expressed in tumor vasculature when compared with vessels in normal tissue.
Tumor vessels specifically express endoglin – CD105, a homodimeric surface component of transforming growth factor (TGF) beta-receptor. Endoglin is highly expressed by endothelial cells of intratumoral vessels but not by pre-existing blood vessels.
VEGF-A and its receptors VEGFR-1 and VEGFR-2 play major roles in physiological as well as pathological angiogenesis, including tumor angiogenesis. VEGF-A and its receptor system exist within vascular endothelial cells, contributing to endothelial functions.
VEGF is a ligand for two VEGF receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1), and the VEGF165 isoform for neuropilin-1. For KDR, vessel density correlated positively to MVD and Chalkley scores (p = 0.01 and 0.04, respectively).
MMRN1, a member of the elastin microfibrillar interface protein (EMILIN)/multimerin family, has so far primarily been described as a component of secretory granules found in platelets and endothelial cells that may mediate cellular adhesion via integrin receptors.
MMRN2, an endothelial specific member of the emilin family and component of the extracellular matrix, was recently found as an extracellular interacting protein for CLEC14A and MMRN2 and CLEC14A were both upregulated in tumour vasculature during tumour progression.
Endothelial NO synthase (eNOS) can modulate cancer-related events (angiogenesis, apoptosis, cell cycle, invasion, and metastasis).
Endothelial cell activation is defined by the endothelial expression of cell-surface adhesion molecules, such as VCAM-1, ICAM-1, and endothelial leukocyte adhesion molecule (ELAM, also known as E-selectin).
von Willebrand factor (vWF), a glycoprotein produced uniquely by endothelial cells and megakaryocytes, is routinely used to identify vessels in tissue sections. Our data support the measurement of vWF mRNA in tumors to detect activated endothelium or angiogenesis.
Since CCL11 enhances tissue recruitment of eosinophils, an increased concentration of CCL11 should attract more eosinophils and cause more severe eosinophilia in tissues where the concentration of CCL11 is high. Indeed, a study on eosinophilia in colorectal neoplastic lesions showed that tissue extracted from a tumor with a greater number of eosinophils was also highly chemotactic for eosinophils, which was thought to reflect chemokine concentrations in the tissue.
The biological effects of CCL11 are mediated via CC chemokine receptor 3 (CCR3), which is highly expressed on eosinophils and other cells. CCL11 and CCR3 have been shown to be key mediators in the accumulation of eosinophils and in the production of 铿乥rogenic cytokines.
Our findings show that the CXCR2鈥揅XCL1 axis is correlated with CD15+ neutrophil infiltration into both intra- and peri-tumoral regions, and represents an independent prognostic factor in HCC.
The chemokine receptor CXCR2 and its ligands CXCL1, CXCL2 and CXCL5 play an important role in homing of tumor-associated neutrophils (TANs) into developing tumors.
CXCL5 (epithelial neutrophil-activating peptide-78) is a member of a proangiogenic subgroup of the CXC-type chemokine family of small, secreted proteins. CXCL5 promotes HCC cell proliferation, invasion, and intratumoral neutrophil infiltration.
Polymorphonuclear granulocyte (PMN) functions are modulated by a variety of cytokines and chemokines, and many of those factors have been implicated in tumor progression: CXCL8 (interleukin-8) promotes the tumor in铿乴tration by PMNs and has been implicated in the modulation of the tumor microenvironment.
Correspondingly, lower expression of CXCR1 and CXCR2 was detected for circulating neutrophils. Independently, or in association with other mechanisms, these observations may account for an impaired migration of neutrophils in breast cancer patients upon diagnosis.
Our findings show that the CXCR2鈥揅XCL1 axis is correlated with CD15+ neutrophil infiltration into both intra- and peri-tumoral regions, and represents an independent prognostic factor in HCC.
Mast cell infiltration and activation in tumors were mainly mediated by tumor-derived stem cell factor (SCF) and its receptor c-Kit on mast cells. Low concentrations of SCF efficiently induced the chemotactic migration of mast cells.
High levels of ARG1 expression by MDSCs can accelerate the depletion of L-arginine in the tumour microenvironment, which subsequently inhibits T-cell proliferation by causing low expression of T-cell receptors and thus suppression of the cell cycle in T cells.
These suppressive cells had upregulated expression of gp91phox, an important component of the ROS-generating NADPH oxidase, and the inactivation of ROS was able to abolish the ability of this subset to inhibit T cell responsiveness.
IDO, an intracellular enzyme, activates kynurenine pathway of tryptophan to suppress T-cell proliferation and activate the cellular stress response pathway via the kinase GCN2. Furthermore, tolerogenic kynurenine metabolites bind to aryl hydrocarbon receptor in T cells, resulting in inhibition of T cells-based anticancer immunity. In addition to macrophages, dendritic cells (DCs) and granulocytes, IDO has been found in immature myeloid-derived cells. IDO expression in MDSCs leads to a decreased IFN-纬 release and CD3味-chain expression in T cells.
MDSC also perturb tumor immunity by skewing it toward a tumor-promoting type 2 phenotype. They do this by producing the type 2 cytokine IL-10 and by down-regulating macrophage production of the type 1 cytokine IL-12.
IL4I1 is a secreted L-amino acid oxidase that mainly catabolizes L-phenylalanine to produce hydrogen peroxide, ammonia, and phenylpyruvate. In the past 10 years, IL4I1 has been shown to be expressed by tumor-associated macrophages (TAMs) of numerous cancer types and to regulate T-cell properties both in vitro and in vivo.
Here we demonstrated that circulating CD11b+CD14+HLA-DR鈭捖燾ells were significantly increased in esophageal SCC patients compared with healthy people, and this was associated with the clinical stage, treatment response and circulating IL-6 levels. IL-6 stimulated reactive oxygen species, arginase 1 and p-STAT3 in MDSCs.
In the present study, we report that the establishment of a positive feedback loop between prostaglandin E(2) (PGE(2)) and cyclooxygenase 2 (COX2), the key regulator of PGE(2) synthesis, represents the determining factor in redirecting the development of CD1a(+) DCs to CD14(+)CD33(+)CD34(+) monocytic MDSCs. The addition of PGE(2) to GM-CSF/IL-4-supplemented monocyte cultures is sufficient to induce the MDSC phenotype and cytotoxic T lymphocyte (CTL)-suppressive function. In accordance with the key role of PGE(2) in the physiologic induction of human MDSCs, the frequencies of CD11b(+)CD33(+) MDSCs in ovarian cancer are closely correlated with local PGE(2) production, whereas the cancer-promoted induction of MDSCs is strictly COX2 dependent. The disruption of COX2-PGE(2) feedback using COX2 inhibitors or EP2 and EP4 antagonists suppresses the production of MDSC-associated suppressive factors and the CTL-inhibitory function of fully developed MDSCs from cancer patients.
ChemR23, the receptor for chemerin and resolvin E1, is expressed and functional on M1 but not on M2 macrophages.
Classical or M1 macrophages are generally considered to be potent effector cells which kill tumor cells by producing nitric oxide and reactive oxygen. They also produce copious amounts of pro-inflammatory cytokines, such as IL-12, IL-23 and IFN-纬.
Classical or M1 macrophages are generally considered to be potent effector cells which kill tumor cells by producing nitric oxide and reactive oxygen. They also produce copious amounts of pro-inflammatory cytokines, such as IL-12, IL-23 and IFN-纬.
M1 macrophages are characterized by the production of pro-inflammatory cytokines like TNF-伪, IL-1尾, IL-6 and IL-12.
Classical or M1 macrophages are generally considered to be potent effector cells which kill tumor cells by producing nitric oxide and reactive oxygen. They also produce copious amounts of pro-inflammatory cytokines, such as IL-12, IL-23 and IFN-纬.
We found that IRF5 was indeed a major factor in defining macrophage polarization: it had high expression in M1 macrophages and induced a characteristic gene-expression and cytokine-secretion profile and promoted robust TH1-TH17 responses.
The NO burst of the M1 macrophages is due to the increased expression of the NOS2 (also called inducible NOS) isoform, rather than to the rise in the NO synthesis of constitutively expressed NOS isoforms.
A key role for SOCS3 in M1 polarization is proposed.
Inflammatory M1 macrophages produce many other pro-inflammatory cytokines like TNF伪, IL-1, IL-6, IL-12, Type I IFN, CXCL1-3, CXCL-5, and CXCL8-10.
Macrophage infiltration into tumors is regulated by a number of cytokines and chemokines, in particular MCP-1. MCP-1 is a member of the C-C chemokine family and possesses chemotaxic activity for monocytes and T lymphocytes.
Furthermore, CCL7 is more abundant in metastatic tumor site than in the primary site, and is associated with macrophage infiltration in tumor.
CCL8, also designated as monocyte chemotactic protein 2 (MCP2), belongs to the CC chemokines. It is strongly induced by IFN-纬24 and is one of the most potent chemoattractants for mononuclear cells, including monocytes and T cells. Thus, CCL8 may contribute to the histiocyte-rich (and T-cell rich) composition of the microenvironment in THRLBCL.
Among these chemokines, MCP-1, which binds only CC chemokinereceptor 2 (CCR2), is one of the most potent macrophage-recruitment factors. MCP-1 is produced by a variety of cells including fibroblasts, endothelial cells, smooth muscle cells and monocytes/macrophages. Moreover, MCP-1 expression is associated with monocyte recruitment in human glioma, breast, ovarian and prostate carcinoma.
Colony stimulating factor-1 (CSF1) is a key cytokine involved in recruitment and activation of tissue macrophages, exerting these effects through binding to a high-affinity receptor tyrosine kinase, the cFMS/CSF1 receptor (CSF1R).
Colony stimulating factor-1 (CSF1) is a key cytokine involved in recruitment and activation of tissue macrophages, exerting these effects through binding to a high-affinity receptor tyrosine kinase, the cFMS/CSF1 receptor (CSF1R).
With the recognition of cross-presenting DCs as the only cells bearing XCR1, this concept can be further refined. Thus, in the early innate response, XCL1 may ensure contact and thus exchange of information between activated NK cells and XCR1-bearing DCs. Later, in the adaptive phase and on reexposure, this cytokine functional unit is handed over to CD8+ T cells and thus ensures proper communication between cross-presenting DCs and CD8+ T cells, as also demonstrated experimentally.
With the recognition of cross-presenting DCs as the only cells bearing XCR1, this concept can be further refined. Thus, in the early innate response, XCL1 may ensure contact and thus exchange of information between activated NK cells and XCR1-bearing DCs. Later, in the adaptive phase and on reexposure, this cytokine functional unit is handed over to CD8+ T cells and thus ensures proper communication between cross-presenting DCs and CD8+ T cells, as also demonstrated experimentally.
Collagen XI is a minor collagen whose main physiologic function is to regulate the diameter of major collagen fibrils. Recent research has highlighted the importance of colXI伪1 in many types of cancer, including its roles in metastasis, angiogenesis, and drug resistance, as well as its potential utility in screening tests and as a therapeutic target. High levels of colXI伪1 overexpression have been reported in multiple expression profile studies examining differences between cancerous and normal tissue, and between beginning and advanced stage cancer. Its expression has been linked to poor progression-free and overall survival. The consistency of these data across cancer types is particularly striking, including colorectal, ovarian, breast, head and neck, lung, and brain cancers.
Type I collagen, found in most connective tissue and embryonic tissue, is an important member of the collagen family which is a key structural component of the extracellular matrix. Typically, type I collagen is composed of two chains of collagen type I alpha 1 (COL1A1) and one chain of collagen type I alpha 2 (COL1A2). Recently, similar to the expressions of other members of the collagen family which is believed to be involved in carcinogenesis, abnormal expression of COL1A1 and COL1A2 has been reported in several cancers.
Type I collagen, found in most connective tissue and embryonic tissue, is an important member of the collagen family which is a key structural component of the extracellular matrix. Typically, type I collagen is composed of two chains of collagen type I alpha 1 (COL1A1) and one chain of collagen type I alpha 2 (COL1A2). Recently, similar to the expressions of other members of the collagen family which is believed to be involved in carcinogenesis, abnormal expression of COL1A1 and COL1A2 has been reported in several cancers.
Collagen Type III Alpha 1 Chain (COL3A1), encodes the pro-alpha1 chains of type III collagen, a fibrillar collagen that is found in extensible connective tissues such as skin, lung, uterus, intestine and the vascular system, frequently in association with type I collagen. The family of collagen was also reported to play a critical role in tumor progression, migration and proliferation.
The heterotrimers formed by COL4A1 and COL4A2 presents in almost all the basement membranes, which are a specialized form of the extracellular matrix. Besides that the basement membranes can mediate tissue compartmentalization and transfer environmental signals to epithelial cells, it is also an important structural and functional component of blood vessels.
We found a marked increase both in the absolute amount of Type V collagen and in the ratio of Type V collagen to the other interstitial collagens in the desmoplastic stroma, compared with benign breast tissue.
The tissue is stiffer than normal, reflecting increased deposition and crosslinking of collagen and elastin. Mature elastin is a highly crosslinked structure containing the unique crosslinking amino acids, desmosine and isodesmosine.
FN is a major ECM constituent that binds to adhesion receptors on multiple cell types. FN supports cell鈥揈CM interactions and is essential for wound healing, development, and maintaining tissue homeostasis. The expression of FN is elevated in many solid tumors, particularly PDA. Various cell types including cancer cells and endothelial cells can produce FN, although it is primarily secreted by fibroblasts.
Laminin-332, an extracellular matrix (ECM) component composed of LAMA3, LAMB3, and LAMC2 chains, is expressed by both tumor and stromal cells. Laminin-332 expression is increased in several types of tumors. During tumor progression, laminin-332 binds to integrin 伪6尾4, specifically the 尾4 subunit, and signals through the PI3K and RAC1 pathways to promote the survival, invasion, and directional migration of tumor cells.
Laminin-332, an extracellular matrix (ECM) component composed of LAMA3, LAMB3, and LAMC2 chains, is expressed by both tumor and stromal cells. Laminin-332 expression is increased in several types of tumors. During tumor progression, laminin-332 binds to integrin 伪6尾4, specifically the 尾4 subunit, and signals through the PI3K and RAC1 pathways to promote the survival, invasion, and directional migration of tumor cells.
Laminin-332, an extracellular matrix (ECM) component composed of LAMA3, LAMB3, and LAMC2 chains, is expressed by both tumor and stromal cells. Laminin-332 expression is increased in several types of tumors. During tumor progression, laminin-332 binds to integrin 伪6尾4, specifically the 尾4 subunit, and signals through the PI3K and RAC1 pathways to promote the survival, invasion, and directional migration of tumor cells.
Members of the galectin family are recognized for their ability to bind 尾-galactosides via their carbohydrate recognition domain (CRD). Unlike other galectins, gal-7 is strictly expressed in epithelial cells. In fact, this galectin is generally considered to be a marker of epithelial differentiation. Gal-7 expression correlated with a significant difference in the overall survival of patients with ovarian serous cystadenocarcinoma.
Galectin-9 expression is frequently altered in cancer as compared to normal tissues. In addition, an increasing amount of evidence suggests that galectin-9 is involved in several aspects of tumor progression, including tumor cell adhesion and survival, galectin-9 expression is widely distributed in tissues involved in the immune system, i.e. spleen, thymus and peripheral blood lymphocytes, and in tissues of endodermal origin, i.e. liver, intestine, stomach and lung. immune escape and angiogenesis. Indeed, several groups have now shown that galectin-9 levels vary when comparing tumor tissue to normal tissue. A high or increased galectin-9 expression has only been reported in leukemia and colon cancer cell lines.
TN is an extracellular matrix glycoprotein with a unique six-armed macromolecular structure, which is known to be an essential factor for modulation of reciprocal interactions between the epithehium and mesenchyme during embryogenesis. A number of studies have demonstrated prominent TN expression in human cancers including those of brain, colon, liver, lung, uterus, skin, prostate, and mammary gland.
The human serum component vitronectin (VN), also termed serum spreading factor and complement S-protein, is a 75-kDa adhesive glycoprotein, which plays important roles in inflammation, cell adhesion, cell necrosis, and blood coagulation. As a major component or master organizer of extracellular matrix (ECM), VN has been found to regulate vascular endothelial growth factor (VEGF)-induced angiogenesis, a key step in tumor formation. Importantly, VN was reported to play a key role in the development and progression of solid tumors including breast cancer.
ADAMTSs are a family of secreted proteinases that share the metalloproteinase domain with matrix metalloproteinases (MMPs). The results of this study support the notion that ADAMTS-4 and -5 are over-expressed in CRC possibly for tissue disruption that would facilitate cancer cell invasion and metastasis.
ADAMTSs are a family of secreted proteinases that share the metalloproteinase domain with matrix metalloproteinases (MMPs). The results of this study support the notion that ADAMTS-4 and -5 are over-expressed in CRC possibly for tissue disruption that would facilitate cancer cell invasion and metastasis.
CA IX has been found overexpressed by cancer cells from many tumor types, being a component of the pH regulatory system exploited by these cells to counteract the harmful effects of an highly glycolytic metabolism.
Lysyl oxidase (LOX) has been reported to regulate tumor metastasis and has been found to involve in modification of extracellular matrix (ECM) in the context of tumorigenesis. LOX, an extracellular copper-dependent amine oxidase, catalyzes the exchange of an amine to aldehyde group on a peptidyl lysine, producing hydrogen peroxide (H2O2) and ammonia as by-products of catalytic activity. The function of LOX is the covalent cross-linking of collagens or elastin to increase ECM tensile strength.
MMP1 is the most highly expressed interstitial collagenase degrading fibrillar collagens. Overexpression of MMP1 has been shown in tumor tissues and has been suggested to be associated with tumor invasion and metastasis. MMP1 is up-regulated in a wide variety of advanced cancers and has been suggested to be associated with tumor invasion and metastasis. A significant negative correlation between its expression and cancer survival has been found.
Stromelysin-3/matrix metalloproteinase 11 (ST3/MMP11) is associated with tumor invasion and poor prognosis. ST3 is a connective tissue鈥揹erived factor normally expressed in association with intense tissue remodeling during embryogenesis, tissue involution, wound healing, and metamorphosis. We present novel evidence that adipocytes present at human breast tumor invasive front are induced by cancer cells to express ST3.
MMP12 could facilitate the initiation and progression of tumor invasion and metastasis through its ability to degrade a broad spectrum of ECM components including type IV collagen, fibronectin, laminin, vitronectin V, proteoglycans, chondrontin sulfate and myelin basic protein. However, data describing the role of MMP-12 in human malignancies is limited. MMP-12 expression has been found to be activated or enhanced by oncogenic proteins associated with tumor invasion and metastasis in hepatocellular cancer, gynecological cancer, prostate cancer, colorectal cancer, endometrial cancer, and glioma. In addition, MMP-12 has also been reported to regulate tumor angiogenesis, and may be required to activate the angiogenic switch that occurs during tumor neovascularization.
Increased expression of matrix metalloproteinase-2 (MMP-2) predicts tumour recurrence and unfavourable outcome in non-small cell lung cancer.
MMP3 may induce hyperplastic growth via its HPX domain even in the complete absence of the catalytic domain.
Among these, matrix metalloproteinase-7 (MMP-7) (matrilysin) is the smallest (28 kDa) member of the MMP family. It has broad substrate specificity against ECM components, including elastin, type IV collagen, fibronectin, vitronectin, aggrecan, and proteoglycans. In addition, recent studies have also shown that MMP-7 is also involved in the regulation of several bioactive substances other than ECM. MMP-7 plays an important role in ectodomain shedding of cell-surface molecules, such as epidermal growth factor receptor (EGFR), heparin binding epidermal growth factor (HB-EGF), Fas ligand and E-cadherin. These studies demonstrated MMP-7 to have multiple biological functions, such as tumor invasion and metastasis.
MMP9 is specifically required for invasion in cell culture and for pulmonary metastasis in a mouse orthotopic model of basal-like breast cancer. We also find that tumor cell-produced MMP-9 promotes tumor vascularization with only modest impact on primary tumor growth, and that silencing of MMP-9 expression in tumor cells leads to an altered transcriptional program consistent with reversion to a less malignant phenotype. MMP-9 is most highly expressed in human basal-like and triple negative tumors, where our data suggest that it contributes to metastatic progression.
PLOD2 is a hypoxia-induced gene and encodes an enzyme that induces hydroxylation of lysine residues on collagen intracellularly prior to the formation of triple helical procollagen molecules. In the analysis of pancreatic cancer specimens, stromal expression of PLOD2 was found in cancer tissue, not in normal tissue.
Beta-2 microglobulin (B2M) is synthesized in all nucleated cells and forms the light chain subunit of the major histocompatibility complex (MHC) class I antigen.
HLA molecules present pathogen and tumour-derived peptides to T-cells thereby initiating the adaptive immune response. The classical HLA class I molecules, HLA-A, -B and -C, are heterodimers of a polymorphic 伪-polypeptide chain and 尾2-microglobulin, present endogenous peptides to cytotoxic CD8 positive T-cells (CD8+ T-cells), and are expressed by almost all somatic cells.
HLA molecules present pathogen and tumour-derived peptides to T-cells thereby initiating the adaptive immune response. The classical HLA class I molecules, HLA-A, -B and -C, are heterodimers of a polymorphic 伪-polypeptide chain and 尾2-microglobulin, present endogenous peptides to cytotoxic CD8 positive T-cells (CD8+ T-cells), and are expressed by almost all somatic cells.
HLA molecules present pathogen and tumour-derived peptides to T-cells thereby initiating the adaptive immune response. The classical HLA class I molecules, HLA-A, -B and -C, are heterodimers of a polymorphic 伪-polypeptide chain and 尾2-microglobulin, present endogenous peptides to cytotoxic CD8 positive T-cells (CD8+ T-cells), and are expressed by almost all somatic cells.
NLRC5 localizes to the nucleus of lymphocytes, where it promotes MHC class I gene expression via stimulation of the H-2D and H-2K gene promoters. MHC class I molecules have a critical role in tumor immune evasion and are associated with cancer prognosis; since, NLRC5 was reported to act as a MHC class I transactivator, it may therefore affect tumor patients' survival through regulating tumor immune evasion through MHC class I.
TAP2 forms a heterodimer with TAP1 in order to transport peptides (ranging from ions to large proteins) from the cytoplasm to the endoplasmic reticulum, and is essential for loading of antigen on HLA class I protein on the cell surface.
TAP2 (transporter 2, ATP-binding cassette, sub-family B) is a member of the multidrug resistance protein (MRP)/TAP subfamily of ATP-binding cassette (ABC) transporters, and is involved in both multidrug resistance and antigen presentation. TAP2 forms a heterodimer with TAP1 in order to transport peptides (ranging from ions to large proteins) from the cytoplasm to the endoplasmic reticulum, and is essential for loading of antigen on HLA class I protein on the cell surface.
We suggest therefore, that the 48 kDa species functions as a bridge connecting class I molecules and TAP, and propose that it be named tapasin, for TAP-associated glycoprotein. Based on these data and studies of the composition of TAP-associated class I complexes in wild-type cells, we suggest an assembly pathway for class I鈥損eptide complexes that involves association with calreticulin, tapasin, and TAP prior to peptide loading.
A functional CIITA gene is necessary for class II induction, and transfection of CIITA is sufficient to activate expression of MHC class II genes in class II-negative cells in the absence of IFN-gamma. CIITA is therefore a general regulator of both inducible and constitutive MHC class II expression.
HLA-DM is essential in the intracellular assembly of HLA class II-antigenic peptide complexes. It displaces CLIP from the antigen binding groove of HLA class II molecules, to make this groove accessible for loading of antigens. Lack of HLA-DM results in an apparently normal cell surface expression of HLA class II, but without presentation of antigens and neo-antigens.
HLA-DM is essential in the intracellular assembly of HLA class II-antigenic peptide complexes. It displaces CLIP from the antigen binding groove of HLA class II molecules, to make this groove accessible for loading of antigens. Lack of HLA-DM results in an apparently normal cell surface expression of HLA class II, but without presentation of antigens and neo-antigens.
In contrast, the HLA class II molecules HLA-DR, -DQ and -DP are heterodimers of 伪 and 尾-polypeptide chains, present endocytosed extracellular peptides to helper CD4 positive T-cells (CD4+T-cells), and are normally expressed only on antigen presenting cells. DQA1 and DQB1 genes encode the 伪- and 尾-chains of the HLA-DQ heterodimer and, similarly, DPA1 and DPB1 genes encode the respective chains of the DP heterodimer.
In contrast, the HLA class II molecules HLA-DR, -DQ and -DP are heterodimers of 伪 and 尾-polypeptide chains, present endocytosed extracellular peptides to helper CD4 positive T-cells (CD4+T-cells), and are normally expressed only on antigen presenting cells. DQA1 and DQB1 genes encode the 伪- and 尾-chains of the HLA-DQ heterodimer and, similarly, DPA1 and DPB1 genes encode the respective chains of the DP heterodimer.
In contrast, the HLA class II molecules HLA-DR, -DQ and -DP are heterodimers of 伪 and 尾-polypeptide chains, present endocytosed extracellular peptides to helper CD4 positive T-cells (CD4+T-cells), and are normally expressed only on antigen presenting cells. DQA1 and DQB1 genes encode the 伪- and 尾-chains of the HLA-DQ heterodimer and, similarly, DPA1 and DPB1 genes encode the respective chains of the DP heterodimer.
In contrast, the HLA class II molecules HLA-DR, -DQ and -DP are heterodimers of 伪 and 尾-polypeptide chains, present endocytosed extracellular peptides to helper CD4 positive T-cells (CD4+T-cells), and are normally expressed only on antigen presenting cells. DQA1 and DQB1 genes encode the 伪- and 尾-chains of the HLA-DQ heterodimer and, similarly, DPA1 and DPB1 genes encode the respective chains of the DP heterodimer.
In contrast, the HLA class II molecules HLA-DR, -DQ and -DP are heterodimers of 伪 and 尾-polypeptide chains, present endocytosed extracellular peptides to helper CD4 positive T-cells (CD4+T-cells), and are normally expressed only on antigen presenting cells. All have a single DRA gene and a DRB1 gene but some haplotypes have an additional, functional DRB3, DRB4, or DRB5 gene.
In contrast, the HLA class II molecules HLA-DR, -DQ and -DP are heterodimers of 伪 and 尾-polypeptide chains, present endocytosed extracellular peptides to helper CD4 positive T-cells (CD4+T-cells), and are normally expressed only on antigen presenting cells. All have a single DRA gene and a DRB1 gene but some haplotypes have an additional, functional DRB3, DRB4, or DRB5 gene.
Loss of SMAD4 from colorectal cancer cells promotes CCL15 expression to recruit CCR1+ myeloid cells and facilitate liver metastasis.
We further found that hypoxia-inducible factors activate the transcription of chemokine (C-C motif) ligand 26 in cancer cells to recruit chemokine (C-X3-C motif) receptor 1-expressing MDSCs to the primary tumor.
Macrophage colony-stimulating factor (M-CSF or CSF1) is a potent growth factor that promotes the differentiation, proliferation, and migration of monocytes/macrophages via signaling through its receptor tyrosine kinase CSF1R (cFMS). Our results highlight the importance of CSF1/CSF1R signaling in the recruitment of tumor-infiltrating myeloid cells which can limit the efficacy of radiotherapy.
Macrophage colony-stimulating factor (M-CSF or CSF1) is a potent growth factor that promotes the differentiation, proliferation, and migration of monocytes/macrophages via signaling through its receptor tyrosine kinase CSF1R (cFMS). Our results highlight the importance of CSF1/CSF1R signaling in the recruitment of tumor-infiltrating myeloid cells which can limit the efficacy of radiotherapy.
This evidence raises the possibility that GM-CSF, a cytokine broadly usedin cancer patientsforits properties on bone marrow mobilization and immune functions, may promote the expansion of myeloid suppressive components, with negative consequences on tumor antigen鈥搒pecific immune responses.
This evidence raises the possibility that GM-CSF, a cytokine broadly usedin cancer patientsforits properties on bonemarrowmobilization and immune functions, may promote the expansion of myeloid suppressive components, with negative consequences on tumor antigen– specific immune responses.
It has been previously shown that tumor derived factors such as IL-6 and G-CSF are able to facilitate MDSC growth, that increased tumor burden correlated with increased G-CSF and that blockade of G-CSF inhibited tumor growth.
It has been previously shown that tumor derived factors such as IL-6 and G-CSF are able to facilitate MDSC growth, that increased tumor burden correlated with increased G-CSF and that blockade of G-CSF inhibited tumor growth.
PGE(2)-induced CXCL12 production and CXCR4 expression controls the accumulation of human MDSCs in ovarian cancer environment. Frequencies of CD11b+CD14+CD33+CXCR4+ MDSCs closely correlated with CXCL12 and PGE2 levels in patient ascites.
Indeed, we found that PMN-MDSC correlated with intratumor levels of IL-1尾, IL-8, CXCL-5 and Mip-1伪. These data suggest that these chemokines and IL-1 尾 promote accumulation of PMN-MDSC in the parenchyma of the RCC host. CXCR2, the receptor for IL-8 and CXCL-5, was expressed in over 50% of PMN-MDSC.
Indeed, we found that PMN-MDSC correlated with intratumor levels of IL-1尾, IL-8, CXCL-5 and Mip-1伪. These data suggest that these chemokines and IL-1 尾 promote accumulation of PMN-MDSC in the parenchyma of the RCC host. CXCR2, the receptor for IL-8 and CXCL-5, was expressed in over 50% of PMN-MDSC.
Indeed, we found that PMN-MDSC correlated with intratumor levels of IL-1尾, IL-8, CXCL-5 and Mip-1伪. These data suggest that these chemokines and IL-1 尾 promote accumulation of PMN-MDSC in the parenchyma of the RCC host. CXCR2, the receptor for IL-8 and CXCL-5, was expressed in over 50% of PMN-MDSC.
PGE(2)-induced CXCL12 production and CXCR4 expression controls the accumulation of human MDSCs in ovarian cancer environment. Frequencies of CD11b+CD14+CD33+CXCR4+ MDSCs closely correlated with CXCL12 and PGE2 levels in patient ascites.
Here we demonstrated that circulating CD11b+CD14+HLA-DR− cells were significantly increased in esophageal SCC patients compared with healthy people, and this was associated with the clinical stage, treatment response and circulating IL-6 levels. In a 4-NQO-induced esophageal tumor animal model, MDSC recruitment was associated with invasive esophageal tumors and with increased IL-6 levels. IL-6 stimulated reactive oxygen species, arginase 1 and p-STAT3 in MDSCs. Blockade of IL-6 prevented induction of MDSCs and the incidence of 4-NQO-induced invasive tumors.
Here we demonstrated that circulating CD11b+CD14+HLA-DR− cells were significantly increased in esophageal SCC patients compared with healthy people, and this was associated with the clinical stage, treatment response and circulating IL-6 levels. In a 4-NQO-induced esophageal tumor animal model, MDSC recruitment was associated with invasive esophageal tumors and with increased IL-6 levels. IL-6 stimulated reactive oxygen species, arginase 1 and p-STAT3 in MDSCs. Blockade of IL-6 prevented induction of MDSCs and the incidence of 4-NQO-induced invasive tumors.
Biologically, CD177 is a glycosylphosphatidylinositol-linked cell surface antigen that may help mediate neutrophil adherence to the endothelium through its binding of platelet endothelial cell adhesion molecule 1 on endothelial cells. CD177 is also required for proteinase 3 expression on the neutrophil cell surface.
Neutrophil elastase, proteinase 3, and cathepsin G are three hematopoietic serine proteases stored in large quantities in neutrophil cytoplasmic azurophilic granules.
CXCR1 is a central receptor for neutrophil recruitment and activation, supported by the importance of its cognate ligand CXCL8 in a variety of inflammatory diseases.
The present findings suggest that CXCR2 is responsible for neutrophil chemotaxis and margination induced by IL-8.
Secondary granules form during the myelocyte to metamyelocyte transition followed by the formation of tertiary granules during the band cell to segmented cell stage. These granules compartmentalize an arsenal of defensive factors and enzymes, such as myeloperoxidase, elastase, defensins, cathelicidins and matrix metalloproteinases (MMPs), that protect against opportunistic infections and mediate the resolution of inflammation.
Fc纬RIIIb is expressed only by neutrophils and Fc纬RIIIb-neutrophil antigen (NA)1/NA2 polymorphism influenced phagocytosis of immunoglobulin G1-opsonized particles.
Recently, SCFAs, particularly acetate (C2) and propionate (C3), have been found to bind and activate the G-protein-coupled receptor GPR43. Using an extensive data set of human and mouse immune cell transcription profiles we found that transcripts for human GPR43 and mouse Gpr43 exhibited enhanced expression in neutrophils and eosinophils.
Besides cytokines, neutrophils also secrete myeloperoxidase (MPO), also important for recruitment of monocytes/macrophages and activation of platelets.
In summary, mammalian PGRP binds to PGN and Gram-positive bacteria (with unmodified PGN) with nanomolar affinity, is expressed in neutrophils, and inhibits growth of Gram-positive bacteria. Therefore, PGRP may function as an intracellular antibacterial protein in neutrophils.
Neutrophil elastase, proteinase 3, and cathepsin G are three hematopoietic serine proteases stored in large quantities in neutrophil cytoplasmic azurophilic granules.
CD160 is an Ig-like activating natural killer (NK) cell receptor expressed on the majority of circulating NK cells and on a subset of circulating cytotoxic T cells, but not on B cells or EBV-transformed B-cell lines.
Activating receptor. Its ligands are CD112 and CD155, which are members of the Nectin family of molecules and are broadly distributed on haematopoietic and non-haematopoietic cells, including on many tumour cells.
CD244 signalling is mediated by its cytoplasmic immunoreceptor tyrosine-based switch motifs (ITSM). In humans, CD244 interactions with its ligand CD48 result in cytotoxicity and cytokine production. CD244 can also enhance signals by other NK receptors such as NKp30 and NKp46 thereby acting as a costimulator.
Interestingly, we also observed that NK cells from patients with metastatic melanoma expressed reduced levels of Eomes.
Ksp37 expression was limited to Th1-type CD4(+) T cells, effector CD8(+) T cells, gammadelta T cells, and CD16(+) NK cells. Most of these Ksp37-expressing cells coexpressed perforin, indicating that Ksp37 is selectively and commonly expressed in the lymphocytes that have cytotoxic potential.
Granulysin was first known as an intracellular cytolytic molecule within granules of CTLs and NK cells. Originally, the cytolytic function of granulysin was demonstrated in cells infected with intracellular organisms such as Mycobacterium tuberculosis; this molecule was later shown to also be effective against tumor cells.
NK cells recognize and kill their targets by several mechanisms including the release of cytotoxic granules containing PRF1/perforin and GZMB.
Granzyme H (GZMH) is a functional cytotoxic serine protease of NK cell granules, which expands the cell death-inducing repertoire of innate immune system. GZMH is constitutively and highly expressed in human NK cells, in order to possess chymotrypsin-like (chymase) enzymatic activity.
NK cells are an early and potent producer of IFN纬, which has many effects on the immune response, including induction of MHC class II molecules on antigen-presenting cells, activation of myeloid cells and induction of T helper 1 (TH1) cells, as well as effects on angiogenesis.
KIR2DL4 (CD158d): An activation receptor for HLA-G. Although it has a long cytoplasmic tail that is typical of inhibitory KIR, engagement of this receptor results in the activation of NK cells, not for cytotoxicity, but for cytokine and chemokine secretion.
We hypothesized that CMV-induced CD56dimCD57+NKG2C+ NK cells with enhanced function and long-term persistence may promote cancer control in transplant recipients.
NKp80, an activating homodimeric C-type lectin-like receptor (CTLR), is expressed on essentially all human natural killer (NK) cells and stimulates their cytotoxicity and cytokine release.
Activating receptor. NKG2D ligands are MICA, MICB, RAET1E, RAET1G, RAET1H, RAET1I, RAET1L and RAET1N. They can be expressed on rapidly proliferating cells, infected cells, transformed cells and tumour cells.
NCR1 is expressed constitutively on NK cells. Transmits its activating signal by associating with the ITAM-bearing adaptor protein CD3味 and Fc蔚RI纬.
NKp30, NKp44, and NKp46 are the most well characterized NCRs. Our results show for the first time that the numbers of NKp30 and NKp46-positive NK cells were significantly reduced in almost all patients with PC, GC, and CRC, consistent with studies in other malignancies such as cervical cancer, breast cancer, and melanoma. It has been reported that NCR-positive NK cells have the ability to kill harmful cells, such as transformed malignant cells and infected cells, and can also secret inflammatory cytokines such as interferon-纬 (IFN-纬) and tumor necrosis factor-伪 (TNF-伪). Accordingly, the lower number of cells expressing NKp30 and NKp46 may be partly responsible for the poor function of NK cells in patients with PC, GC, and CRC.
Analysis of the subcellular localization of GMP-17 during activation of NK cells reveals that GMP-17 is relocalized from granules to the plasma membrane, suggesting that GMP-17 may contribute to the effector function of cytotoxic lymphocytes.
We show that recruitment of EAT-2 mediates the phosphorylation of CRACC, possibly by recruiting a Src kinase, and we define the signaling mediators downstream of CRACC/EAT-2 implicated in triggering NK cell-mediated cytotoxicity.
IL-10 is a crucial mediator of inflammation, apoptosis, Th1/ Th2 balance, and functions as autocrine growth factor in lymphoid tumors. Our finding of an adverse prognostic impact of increased IL-10 serum levels is in accordance with previous reports in high and intermediate NHL. Correlation between tumor mass indicators (advanced stage, medullar involvement, and high FLIPI score) and IL-10 serum levels suggests that tumor B cells might be the source of this anti-inflammatory cytokine.
Based on the present understandings of IL-22 biology, it is believed that IL-22 is important in enhancing innate immunity response, tissue damage protection and tissue repair.
MSCs support FL B-cell viability through their expression of adhesion molecules and integrins, which provide survival signals to the FL B-cells upon binding to their cognate receptors, as well as by their elaboration of pro-survival cytokines such as IL-6 and BAFF.
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine, which was shown to be upregulated in cancers and to exhibit tumor promoting properties. Unlike other cytokines, MIF is ubiquitously present in the circulation and tissue of healthy subjects. We recently described a previously unrecognized, disease-related isoform of MIF, designated oxMIF, which is present in the circulation of patients with different inflammatory diseases.
TGF-尾 plays an important role in the maintenance of Tregs, their suppressor function and the generation of iTregs and Th17. While TGF-尾 could function directly to mediate Treg suppression of T cell activation, differentiation and proliferation, it could also function in a novel mechanism of infectious tolerance by converting na茂ve T cells into anergic and suppressive cells.
TGF-尾 plays an important role in the maintenance of Tregs, their suppressor function and the generation of iTregs and Th17. While TGF-尾 could function directly to mediate Treg suppression of T cell activation, differentiation and proliferation, it could also function in a novel mechanism of infectious tolerance by converting na茂ve T cells into anergic and suppressive cells.
TGF-尾 plays an important role in the maintenance of Tregs, their suppressor function and the generation of iTregs and Th17. While TGF-尾 could function directly to mediate Treg suppression of T cell activation, differentiation and proliferation, it could also function in a novel mechanism of infectious tolerance by converting na茂ve T cells into anergic and suppressive cells.
The B7-CD28 interaction in particular seems to be one of the major pathways among the variety of ligand-receptor interactions between APC and T cells, leading to long-lasting T-cell activation. Therefore, costimulation by CD28 antibodies may substitute for insuf铿乧ient costimulatory signaling by the malignant B cells.
The 伪尾TCR is noncovalently associated with three dimeric signaling modules: CD3未蔚, CD3纬蔚, and 味味.
The multicomponent assembly of the TCR complex illustrates general principles used by many receptors in the immune system, which rely on basic and acidic transmembrane residues to guide assembly. The intrinsic binding of the cytoplasmic domains of the CD3蔚 and 味 chains to the inner leaflet of the plasma membrane represents a novel mechanism for control of receptor activation: Insertion of critical CD3蔚 tyrosines into the hydrophobic membrane core prevents their phosphorylation before receptor engagement.
The 伪尾TCR is noncovalently associated with three dimeric signaling modules: CD3未蔚, CD3纬蔚, and 味味.
CD5 is a surface glycoprotein expressed on the majority of mature T-cells. It is felt to have a role in thymocyte development and selection, T-cell activation and T-cell antigen presentation.
ITK is a cytoplasmic nonreceptor tyrosine kinase. It is a member of the Tec Kinase family and is essential for T-cell receptor signaling and T-helper cell differentiation.
T-bet is a hallmark transcription factor that is essential for differentiation and function of Th1 cells, CD8+ T cells, 纬未 T cells and NK cells.
Many structures of human and mouse complexes have shown a typical binding mode, which maximizes 伪尾TCR interaction with the MHC-bound peptide. This binding mode places the hypervariable loops of the TCR, the CDR3伪 and CDR3尾 loops, over the center of the bound peptide. Two other TCR loops, CDR1伪 and CDR1尾, frequently also contribute to peptide recognition by binding over amino-terminal and carboxy-terminal peptide segments, respectively.
Thus, TRIM represents a novel TCR-associated polypeptide likely to be involved in recruitment of intracellular signaling proteins to the plasma membrane after T cell activation.
Many structures of human and mouse complexes have shown a typical binding mode, which maximizes 伪尾TCR interaction with the MHC-bound peptide. This binding mode places the hypervariable loops of the TCR, the CDR3伪 and CDR3尾 loops, over the center of the bound peptide. Two other TCR loops, CDR1伪 and CDR1尾, frequently also contribute to peptide recognition by binding over amino-terminal and carboxy-terminal peptide segments, respectively.
Many structures of human and mouse complexes have shown a typical binding mode, which maximizes 伪尾TCR interaction with the MHC-bound peptide. This binding mode places the hypervariable loops of the TCR, the CDR3伪 and CDR3尾 loops, over the center of the bound peptide. Two other TCR loops, CDR1伪 and CDR1尾, frequently also contribute to peptide recognition by binding over amino-terminal and carboxy-terminal peptide segments, respectively.
CD40 ligand (CD40L) is a cell surface costimulatory molecule expressed mainly by activated T cells. CD40L is critically important for T-B cell and T cell-dendritic cell interactions. CD40L expression promotes Th1 cytokine responses to protein Ags and is responsible for Ig isotype switching in B cells.
Initially, it was believed that CD4+ T helper cell type 1 (Th1) lymphocytes, CD8 cytotoxic lymphocytes, and NK cells exclusively produced IFNG. However, there is now evidence that other cells, such as B cells, NKT cells, and professional antigen-presenting cells (APCs) secrete IFNG. Th2-to-Th1 phenotype switch happens when CD4+ cells are treated with IFNG.
Interleukin-12 (IL-12), a heterodimeric cytokine produced by activated monocytes and dendritic cells, plays a crucial role in regulating interferon (IFN)-纬 production and in the generation of IFN鈥撐斥€損roducing T helper 1 (Th1) cells. Here we show that the IL-12 receptor (IL12R) 尾2 subunit, a recently cloned binding and signal transducing component of the IL-12R, is expressed on human Th1 but not Th2 clones and is induced during differentiation of human naive cells along the Th1 but not the Th2 pathway.
IL-2 is critical for the development and peripheral expansion of CD4+CD25+regulatory T cells, which promote self-tolerance by suppressing T cell responses in vivo. IL-2 is produced primarily by activated CD4+ T cells, although expression by naive CD8+ T cells, dendritic cells, and thymic cells has also been reported.
IL-21 is produced by a variety of activated CD4+ T cells including TH1 and TH17 cells, natural killer T (NKT) cells and follicular helper T cells. IL-21 plays a role in the differentiation and proliferation of B cells as well as of CD4+ and CD8+ T lymphocytes. Moreover, IL-21 exerts potent antitumor effects due to its ability to induce and expand cytotoxic CD8+ T cells, NK cells and NKT cells, as well as to its capacity to suppress FOXP3 expression and the expansion of regulatory T cells (Tregs).
These results demonstrate that, as in murine systems, STAT4 is required for optimal human Th1 lineage development.
T-bet, a T-box transcription factor, is required for Thelper (Th) 1 T-cell development from naive T-helper precursor cells (Thp) and redirects Th2 T cells to Th1 development.
The chemokines CCL17 and CCL22 attract CCR4-bearing cells, which are especially polarised to Th2-type cells and regulatory T cells (Treg).
IL-10 is a Th2 product and potent inhibitor of Th1 cells. IL-10 is produced by virtually all leukocytes. In macrophages, IL-10 is elicited in response to TLR activation, glucocorticoids, and C-type lectin signaling. The macrophage transcriptome induced by IL-10 includes selected Fc receptors, the chemoattractants CXCL13 and CXCL4, and the recognition receptors formyl peptide receptor 1 (FPR1), TLR1, TLR8, and macrophage receptor with collagenous domain (MARCO).
At the tumor site Th2 cells release IL-5 and IL-13, cytokines known to contribute to fibrosis by promoting collagen synthesis.
The M2 group of stimuli arose from the initial IL-4 observations, and they are grouped mainly due to their ability to antagonize prototypic inflammatory responses and markers. IL-4 is produced by the Th2 cells, eosinophils, basophils, or macrophages themselves and is recognized by three different receptor pairs.
At the tumor site Th2 cells release IL-5 and IL-13, cytokines known to contribute to fibrosis by promoting collagen synthesis.
We identified CCR8 as the most robustly and differentially expressed chemokine receptor in breast tumor resident Treg cells as compared to peripheral blood Treg cells or Tconv cells found in either peripheral blood or breast tumors.
CTLA-4 proteins contribute to the suppressor function of regulatory T cells (Tregs).
Transcriptional factor Foxp3 serves as a lineage specification factor of Treg cells.
Helios has been suggested to play important roles in immune regulation by repressing pro-apoptotic genes in Tregs, contributing to the development of follicular Tregs, and enhancing Treg function in cooperation with FoxP3. FoxP3+/鈥揌elios+ Tregs are significantly expanded in the peripheral blood and at tumor sites of various cancers, and have been reported to exhibit enhanced in vitro suppressive activity.
In previous studies, EOS was shown to physically interact with FOXP3, repress FOXP3-regulated genes, and mediate Treg-suppressive function, and, of the 5 TFs studied, only EOS appeared to be involved in regulation of FOXP3 independent from FOXP3 mRNA, implying that it may be involved with posttranscriptional control of FOXP3, especially in tumor Tregs.
The majority of tumor-associated IL-10 was produced by an activated Treg population.
While high GITR expression is clearly a marker for Tregs, its function on Tregs is more complex. In general, GITR modulation induces Treg expansion, inhibits Treg suppressive function and promotes Teff resistance to Treg suppression.
Expression of CCR8 and its ligand CCL1 is found outside the central tumor area. An impressive 5-fold increase in the expression of CCL22 (2J) and an average 45-fold increase in the number of CCL1 expressing cells (P<0.05) (2K) was observed in melanoma-affected skin, suggesting that Treg are preferentially attracted towards tumors.
Our results suggest that through two distinct mechanisms, intratumoral TFH induce production of CCL17 and CCL22 by FL tumor cells and facilitate active recruitment of Tregs and IL-4鈥損roducing T cells, which in turn may stimulate more chemokine production in a feed-forward cycle.
Our results suggest that through two distinct mechanisms, intratumoral TFH induce production of CCL17 and CCL22 by FL tumor cells and facilitate active recruitment of Tregs and IL-4鈥損roducing T cells, which in turn may stimulate more chemokine production in a feed-forward cycle.
The liver tumors may evade the host immunosurveillance and maintain the growth advantages by upregulating expression of CCL28 during hypoxia; and by binding to its receptor, CCR10, CCL28 can effectively recruit CCR10+ Treg cells to the tumor site, where this specific population of Treg cells repress the functions of effector T-cells, promoting the in vivo tumor growth.
The liver tumors may evade the host immunosurveillance and maintain the growth advantages by upregulating expression of CCL28 during hypoxia; and by binding to its receptor, CCR10, CCL28 can effectively recruit CCR10+ Treg cells to the tumor site, where this specific population of Treg cells repress the functions of effector T-cells, promoting the in vivo tumor growth.
In light of the differential expression of CCR4 on Tregs and non-Tregs and the knowledge that CCR4 is the only known receptor for CCL17 and CCL22, our data support the development of blocking antibodies or small-molecule antagonists against CCR4 that can be used in combination with other immunotherapeutic strategies in therapies for FL and other B-cell malignancies.
Expression of CCR8 and its ligand CCL1 is found outside the central tumor area. An impressive 5-fold increase in the expression of CCL22 (2J) and an average 45-fold increase in the number of CCL1 expressing cells (P<0.05) (2K) was observed in melanoma-affected skin, suggesting that Treg are preferentially attracted towards tumors.
Aurora A kinase (AAK) is a member of the aurora kinase family and is expressed in all actively dividing cells. Several groups have reported increased AAK expression in aggressive lymphomas, as compared with normal B cells.
Throughout G2, aurora B functions in a protein complex, mainly associating with microtubules near the kinetochores, and is responsible for bipolar attachment of the spindle to the centromeres and correct segregation of the daughter chromatids. Subsequently, aurora B redistributes to the midbody where it has a key role in cytokinesis. Both aurora A and B are overexpressed in a large number of human solid tumors as well as leukemia cell lines and adult AML patients, also showing a correlation with a poor prognosis in these patients.
A far more common event in human tumors may be up-regulation of mitotic factors and several studies have found high Bub1 levels in subsets of breast and gastric cancers, and lymphomas. However, because Bub1 expression is relatively high in proliferating cells compared with quiescent or differentiated cells, increased Bub1 levels may simply represent an increase in the mitotic index of the tumors compared with neighboring tissue.
CCNB1 and CDC2 form a complex, which is essential for the G2/M transition of the cell cycle. This complex has a peak during the G2/M phase and must be degraded before the completion of the cell division.
Cyclin D group includes three members, cyclin D1, cyclin D2, and cyclin D3. Effector role in cell proliferation cascades activated by growth factor signaling is considered to be their main function, and their expression in normal cells is induced during the response to mitogenic stimuli. We found that cyclin D1 expression level is increased in several B-lymphoid neoplasms, such as MCL, BCLL, FL, and DLBCL and MZL compared with reactive cells.
Cyclin E and the cyclin-dependent kinase inhibitor p27 are two important regulators of the G1-S transition modulating the activity of cyclin-dependent kinases. Our data showed a rather strong association between cyclin E expression and proliferation determined by the S-phase fraction and all lymphomas, except aggressive lymphomas, had in principle higher cyclin E index than S-phase fractions.
Because CDK2 regulates cell cycle progression through the interaction with both cyclin E and cyclin A2, its functions extend beyond G1 regulation to control events in S and G2/M phases. Early deregulation of the CDK2 protein in our FL samples could have great impact on the cell cycle with effects extending beyond G1, in light of the broad substrates that CDK2 and its cyclin partners affect.
CETN3 is located at the centrosome of interphase and mitotic cells, where it plays a fundamental role in centrosome duplication.
The E2F family of transcriptional factors modulates the expression of a broad array of genes important for cell cycle progression from G1 to S phase. The E2F-1/DP-1 heterodimer has been shown to regulate genes involved in DNA synthesis (i.e., dihydrofolate reductase, thymidine kinase, and DNA polymerase 伪) and those involved in cell growth (i.e., N-myc, c-myc, IGF-1, and cyclin A).
Cohesin is initially loaded onto DNA in G1 by cohesin loaders (NIPBL and MAU2), but isn鈥檛 established until S-phase when SMC3 is acetylated by ESCO1 and ESCO2.
The minichromosome maintenance (MCM) protein family consists of six members of DNA-binding proteins. MCM proteins stand at the end of many signalling pathways involved in cell proliferation. They ensure that synthesis of DNA is initiated only once during each cell cycle. Mcm2 expression can be used to assess tumour proliferation and may be useful as an additional prognostic marker to refine the prediction of outcome in DLBCL.
Minichromosome maintenance protein 6 (MCM6) is one of six proteins of the MCM family which are involved in the initiation of DNA replication and thus represent a marker of proliferating cells.
This protein is expressed in all cell cycle phases except G0 and may therefore be used as a proliferation marker. It was shown that the MIB-1 positive percentage of cells (so called MIB-1 labeling index (LI)) was significantly higher in Grade 3 follicular lymphoma as compared to Grades 1 and 2. Moreover, patients with a LI below the median had a significantly prolonged time to progression and improved overall survival.
C-myb and B-myb showed a quite different pattem of expression. They were expressed in most cell lines of all neoplastic groups, although their expression was somewhat heterogeneous within each group. These data are in agreement with previous data, suggesting that in mature lymphoid cells, c-myb and B-myb expression correlates with proliferation.
PLK1, a mitotic regulator, important for spindle formation, is a transcriptional regulator of the G2/M cell cycle checkpoint. PLK1 is upregulated in cancer, including FL, and is associated with worse outcome, with interest in PLK1 as a clinical target.
Given the reports on polarized macrophage function and the identification of CD163 as a specific M2 macrophage marker, we investigated the prognostic value of CD163+ and CD68+ macrophage infiltrations in different tumor compartments of primary melanomas from patients with American Joint Committee on Cancer (AJCC) stage I/II melanoma. Additionally, we investigated the prognostic value of sCD163 in serum from the same group of patients.
CD68 is a heavily glycosylated type I transmembrane glycoprotein, which is mainly associated with endosomal/lysosomal compartment. Traditionally, CD68 is exploited as a valuable cytochemical marker to immunostain monocyte/macrophages in the histochemical analysis of inflamed tissues, tumor tissues, and other immunohistopathological applications. CD68 alone or in combination with other cell markers of tumor-associated macrophages showed a good predictive value as a prognostic marker of survival in cancer patients.
Colony-stimulating factor 1 receptor (CSF-1R), which is encoded by the C-FMS proto-oncogene, is a transmembrane receptor tyrosine kinase and is the receptor for colony-stimulating factor 1 (CSF-1, also known as macrophage鈥揷olony-stimulating factor). CSF-1 induces TAMs to polarize toward the M2 phenotype and promote tumor progression.
IL10 is a Th2 product and potent inhibitor of Th1 cells. IL-10 is produced by virtually all leukocytes. In macrophages, IL-10 is elicited in response to TLR activation, glucocorticoids, and C-type lectin signaling. The macrophage transcriptome induced by IL-10 includes selected Fc receptors, the chemoattractants CXCL13 and CXCL4, and the recognition receptors formyl peptide receptor 1 (FPR1), TLR1, TLR8, and macrophage receptor with collagenous domain (MARCO).
IL4I1 is a secreted L-amino acid oxidase that mainly catabolizes L-phenylalanine to produce hydrogen peroxide, ammonia, and phenylpyruvate. In the past 10 years, IL4I1 has been shown to be expressed by tumor-associated macrophages (TAMs) of numerous cancer types and to regulate T-cell properties both in vitro and in vivo.
CD206, also termed as MRC1 (C-type mannose receptor 1), is an M2 macrophage marker in both the mouse and the human.
CD204 is the prototypic member of an expanding family of membrane receptors collectively termed scavenger receptors and a multifunctional receptor that recognizes many different types of negatively charged macromolecules. CD204-positive macrophages could be the tumor-promoting macrophages (M2 macrophages) involved in tumor progression in lung adenocarcinoma.
Sialoadhesin (Sn) is a macrophage-restricted lectin-like receptor with extracellular immunoglobulin-like domains that can function as a cell adhesion molecule. The membrane distal immunoglobulin-like domain binds specifically to oligosaccharides terminating in Neu5Ac伪2,3Gal, a glycosidic linkage that is commonly found on O- and N-linked glycans present on the surface of mammalian cells.