CLEC-1 is a death sensor that limits antigen cross-presentation by dendritic cells and represents a target for cancer immunotherapy
Menée à l'aide de lignées cellulaires et de modèles murins de tumeurs, cette étude démontre que le récepteur CLEC-1 des cellules myéloïdes détecte les cellules mortes par nécrose programmée puis met en évidence un mécanisme par lequel l'absence d'expression de CLEC-1 favorise la réponse antitumorale en réduisant l'accumulation des cellules myéloïdes immunosuppressives dans la tumeur et en augmentant la présentation croisée des antigènes des cellules mortes par les cellules dendritiques
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. CLEC-1 acts as an immune checkpoint in myeloid cells and represents a target for cancer immunotherapy.
Science Advances 2022