CD300ld on pathologically activated neutrophils promotes tumor immune suppression by binding phosphatidylserine on CD8+ T cells
Menée à l'aide de lignées cellulaires et de modèles murins, cette étude met en évidence un mécanisme par lequel la protéine membranaire CD300ld des neutrophiles activés favorise l'immunosuppression tumorale en se liant à la phosphatidylsérine des lymphocytes T CD8+
The immunosuppressive tumor microenvironment remains a major obstacle to successful immunotherapy. Pathologically activated neutrophils, alternatively termed polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), drive tumor immune evasion primarily by inducing CD8+ T cell tolerance. While direct intercellular contact between neutrophils and CD8+ T cells is essential for immunosuppressive activity, the mechanisms mediating this interaction need deeper understanding. We previously reported that CD300ld is required for recruiting PMN-MDSCs into tumors, suppressing T cell activation. Here we show that CD300ld mediates neutrophil-driven contact-dependent suppression of cytotoxic CD8+ T cells by binding to phosphatidylserine (PS). Mice with mutant CD300ld lacking PS-binding capacity exhibit reduced immunosuppressive activity. Blockade of the CD300ld–PS interaction by neutralizing antibodies demonstrates therapeutic efficacy against established tumors and synergizes with anti-PD1. Our findings establish CD300ld–PS-mediated cell contact as a critical mechanism of neutrophil-driven immune evasion, revealing a targetable checkpoint pathway to overcome tumor immune resistance and improve immunotherapy outcomes.
Nature Cancer , article en libre accès, 2026