Published August 29, 2022 | Version v2
Dataset Open

CLEC-1 is a death sensor that limits antigen cross-presentation by dendritic cells and represents a target for cancer immunotherapy

Description

Tumors exploit numerous immune checkpoints including those deployed by myeloid cells to curtail anti-tumor immunity. Here, we show that the C-type lectin receptor CLEC-1 expressed by myeloid cells senses dead cells killed by programmed necrosis. Moreover, we identified TRIM21 as an endogenous ligand over-expressed in various cancers. Interestingly, we observed that in mice CLEC-1 blockade combined with chemotherapy to prolong survival in tumor models. Loss of CLEC-1 reduced the accumulation of immunosuppressive myeloid cells in tumors and invigorated the activation state of dendritic cells (DCs), thereby increasing T cell responses. Mechanistically, we found that the absence of CLEC-1 increased the cross-presentation of dead-cell associated antigens by conventional type-1 DCs. Importantly, we identified anti-human CLEC-1 antagonist antibodies able to enhance anti-tumor immunity in CLEC-1 humanized mice. Altogether, our results demonstrate that CLEC-1 acts as an immune checkpoint in myeloid cells and support CLEC-1 as a novel target for cancer immunotherapy.

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Additional details

Funding

Agence Nationale de la Recherche
IGO - Immunothérapies Grand Ouest ANR-11-LABX-0016