Drouin, Saenz, and Gauttier et al. demonstrated that C-type lectin receptor CLEC-1 on myeloid cells recognized endogenous ligand TRIM21, expressed by programmed necrosis-killed cells, and induced an immunosuppressive TME. Genetic and pharmacological inhibition of CLEC-1 in combination with chemotherapy reduced tumor growth and generated durable antitumor immunity. Loss of CLEC-1 reduced the accumulation of immunosuppressive myeloid cells in tumors, and activated DCs to express proinflammatory cytokines and chemokines, initiating T cell responses. Anti-human CLEC-1 antagonist antibodies enhanced antitumor immunity in CLEC-1 humanized mice.
Contributed by Shishir Pant
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.
Author Info: (1) OSE Immunotherapeutics, Nantes, France. Nantes Universit, INSERM, CHU Nantes, Center for Research in Transplantation and Translational Immunology, UMR 1064, F-44000 Nantes, Fr
Author Info: (1) OSE Immunotherapeutics, Nantes, France. Nantes Universit, INSERM, CHU Nantes, Center for Research in Transplantation and Translational Immunology, UMR 1064, F-44000 Nantes, France. (2) Nantes Universit, INSERM, CHU Nantes, Center for Research in Transplantation and Translational Immunology, UMR 1064, F-44000 Nantes, France. (3) OSE Immunotherapeutics, Nantes, France. (4) Nantes Universit, INSERM, CHU Nantes, Center for Research in Transplantation and Translational Immunology, UMR 1064, F-44000 Nantes, France. (5) OSE Immunotherapeutics, Nantes, France. (6) OSE Immunotherapeutics, Nantes, France. (7) OSE Immunotherapeutics, Nantes, France. (8) OSE Immunotherapeutics, Nantes, France. (9) OSE Immunotherapeutics, Nantes, France. (10) OSE Immunotherapeutics, Nantes, France. (11) Nantes Universit, INSERM, CHU Nantes, Center for Research in Transplantation and Translational Immunology, UMR 1064, F-44000 Nantes, France. (12) Nantes Universit, INSERM, CHU Nantes, Center for Research in Transplantation and Translational Immunology, UMR 1064, F-44000 Nantes, France. (13) OSE Immunotherapeutics, Nantes, France. (14) Nantes Universit, INSERM, CHU Nantes, Center for Research in Transplantation and Translational Immunology, UMR 1064, F-44000 Nantes, France. (15) Nantes Universit, INSERM, CHU Nantes, Center for Research in Transplantation and Translational Immunology, UMR 1064, F-44000 Nantes, France. (16) Nantes Universit, INSERM, CHU Nantes, Center for Research in Transplantation and Translational Immunology, UMR 1064, F-44000 Nantes, France. (17) OSE Immunotherapeutics, Nantes, France. (18) Nantes Universit, INSERM, CHU Nantes, Center for Research in Transplantation and Translational Immunology, UMR 1064, F-44000 Nantes, France. (19) Nantes Universit, INSERM, CHU Nantes, Center for Research in Transplantation and Translational Immunology, UMR 1064, F-44000 Nantes, France. (20) Nantes Universit, INSERM, CHU Nantes, Center for Research in Transplantation and Translational Immunology, UMR 1064, F-44000 Nantes, France. CHU Nantes, Nantes Universit, Laboratoire d'Immunologie, CIMNA, Nantes, France. (21) Nantes Universit, INSERM, CHU Nantes, Center for Research in Transplantation and Translational Immunology, UMR 1064, F-44000 Nantes, France. (22) OSE Immunotherapeutics, Nantes, France. (23) Nantes Universit, INSERM, CHU Nantes, Center for Research in Transplantation and Translational Immunology, UMR 1064, F-44000 Nantes, France.
