case_images: PMC7446533_01
case_images: Radiologic and clinical course of disease. (A) Contrasted computed tomography scans of the chest, abdomen, and pelvis show a metastatic lesion within the right adrenal gland (arrow) before initiation of anti-programmed death ligand 1 (PD-L1) therapy (panel A1), which regressed after 16 cycles of treatment with anti-PD-L1 therapy (panel A2). Repeat computed tomography imaging demonstrated progressive disease in the right adrenal gland before initiation of anti-PD-1 therapy (panel A3), with subsequent improvement after 9 months of anti-PD-1 therapy (panel A4). (B) Timeline of therapies. (C) Sites of biopsies and summary of PD-L1/programmed death ligand 2 (PD-L2) staining. CCRT, concurrent radiotherapy; LNs, lymph nodes; NA, not available.
case_images: PO.17.00049f1.jpg
case_images: PMC7446533_01_PO.17.00049f1.jpg
case_images: F1
case_images: Imaging of the face after 6 weeks showed a PR in the RP space, and body imaging after 8 weeks of treatment showed a PR in both the right axilla and right adrenal gland (Fig 1A). Biopsy samples were obtained at the time of diagnosis (biopsy 1), before repeat treatment with anti-PD-L1 (biopsy 2), before treatment with anti-PD-1 (biopsy 3), and after progression anti-PD-1 therapy (biopsy 4; Fig 1B). After his initial disease progression while receiving anti-PD-L1 therapy, repeat biopsy demonstrated no tumor PD-L1 staining (with limited stromal PD-L1 positivity), and PD-L2 remained strongly positive (70%; Fig 1C).
case_images: Histology of longitudinal specimens. Representative immunohistochemistry images at pretherapy (biopsy 1), and post-therapy (before second anti-programmed death ligand 1 [PD-L1] course; post-PD-L1 therapy A; biopsy 2), at progression/resistance to PD-L1 therapy (before response to nivolumab; post-PD-L1 therapy B; biopsy 3), and at nivolumab resistance (postnivolumab; biopsy 4). H&E, hematoxylin and eosin; PD-L2, programmed death ligand 2.
case_images: PO.17.00049f2.jpg
case_images: PMC7446533_01_PO.17.00049f2.jpg
case_images: F2
case_images: Representative immunohistochemistry samples from each time point are shown in Figure 2.
case_images: Molecular analysis of longitudinal tumor specimens. (A) RNA collected from archival tissue blocks were analyzed by nanoString PanCancer Immune Profiling (730 immune-related genes). Normalized data were compared between the post-therapy A (preresistance) and post-therapy B (postresistance) specimens for log2 fold change. Fold change for genes altered by > 2 log2 units (four-fold change) are shown. (B) Genes involved in the interferon-gamma signaling reactome (www.reactome.org; accession: M965) were selected from the PanCancer Immune Profiling gene set and plotted by fold change. This analysis demonstrated a general decrease in interferon-gamma signaling within the tumor microenvironment at disease progression on anti-programmed death ligand 1 (PD-L1). (C) Simplified schematic of known PD-L1/programmed death ligand 2 (PD-L2) interactions. PD-L1 interacts with programmed death 1 (PD-1) and B7-1 (CD80) to promote immune effector cell suppression, whereas PD-L2 can bind PD-1 and RGMb, promoting effector suppression and respiratory tolerance in lung-resident macrophages, respectively. APCs, antigen-presenting cells; COX2, cyclooxygenase-2.
case_images: PO.17.00049f3.jpg
case_images: PMC7446533_01_PO.17.00049f3.jpg
case_images: F3
case_images: IL6 and PTGS2 (cyclooxygenase-2; Fig 3A). Interferon-gamma-responsive genes demonstrated a global downregulation in the resistant sample, consistent with the predicted effects of a decrease in T-cell activity in the tumor microenvironment (Fig 3B).