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Updated: Aug 20, 2025
Experimental Melanoma Immunotherapy Model Using Tumor Vaccination with a Hematopoietic Cytokine
Published on: February 24, 2023
CLEC-1 is a death sensor that limits antigen cross-presentation by dendritic cells and represents a target for cancer
Marion Drouin1,2, Javier Saenz2, Vanessa Gauttier1
1OSE Immunotherapeutics, Nantes, France.
Abstract:
Tumors exploit numerous immune checkpoints, including those deployed by myeloid cells to curtail antitumor 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 Tripartite Motif Containing 21 (TRIM21) as an endogenous ligand overexpressed in various cancers. We observed that the combination of CLEC-1 blockade with chemotherapy prolonged mouse 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. We identified antihuman CLEC-1 antagonist antibodies able to enhance antitumor immunity in CLEC-1 humanized mice. Together, 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.
Insights
Tumor cells use immune checkpoints like CLEC-1 on myeloid cells to suppress anti-cancer immunity. Blocking CLEC-1 with chemotherapy enhances T cell responses and prolongs survival in mouse models.
Area of Science:
- Immunology
- Cancer Biology
- Cell Biology
Background:
- Tumors utilize immune checkpoints, including those on myeloid cells, to evade anti-tumor immunity.
- Myeloid cell-expressed immune checkpoints are critical regulators of the anti-tumor immune response.
Purpose of the Study:
- To investigate the role of C-type lectin receptor CLEC-1, expressed by myeloid cells, as an immune checkpoint in cancer.
- To identify potential therapeutic strategies targeting CLEC-1 for cancer immunotherapy.
Main Methods:
- Studied the sensing of necrotic cell death by myeloid cell-expressed CLEC-1.
- Identified Tripartite Motif Containing 21 (TRIM21) as a cancer-associated ligand for CLEC-1.
- Evaluated the efficacy of CLEC-1 blockade in combination with chemotherapy in mouse tumor models.
- Assessed the impact of CLEC-1 loss on myeloid cell populations, dendritic cell activation, and T cell responses.
- Investigated the mechanism of antigen cross-presentation by dendritic cells in the absence of CLEC-1.
- Developed and tested anti-human CLEC-1 antagonist antibodies in humanized mouse models.
Main Results:
- CLEC-1 on myeloid cells senses dead cells induced by programmed necrosis.
- TRIM21 was identified as an endogenous ligand for CLEC-1, overexpressed in various cancers.
- Combination of CLEC-1 blockade and chemotherapy significantly prolonged survival in mouse tumor models.
- Loss of CLEC-1 reduced immunosuppressive myeloid cells and enhanced dendritic cell activation, boosting T cell responses.
- Absence of CLEC-1 improved cross-presentation of dead cell-associated antigens by conventional type-1 dendritic cells.
- Anti-human CLEC-1 antibodies enhanced anti-tumor immunity in humanized mice.
Conclusions:
- CLEC-1 functions as a myeloid cell-expressed immune checkpoint that suppresses anti-tumor immunity.
- Targeting CLEC-1, particularly with antagonist antibodies, represents a promising novel strategy for cancer immunotherapy.
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