CD300ld on Neutrophils Drives Immune Suppression and Tumor Growth

Immune checkpoint blockade efficacy can be altered by an immune-suppressive tumor microenvironment (TME) in which polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) play a crucial role, rendering them attractive therapeutic targets in cancer. To investigate genes expressed in PMN-MDSCs that are important for their activation and recruitment, Wang, Zheng, Zhang, and colleagues performed an in vivo CRISPR screen targeting myeloid lineage–specific genes and showed that CD300ld, a surface marker expressed on protumor neutrophils, is critical for recruiting myeloid cells to the TME. Naive neutrophils were found to express CD300ld, with a significant upregulation being observed in PMN-MDSCs from tumor-bearing mice. Functional analysis revealed that knockout of Cd300ld in mouse models of melanoma, lung cancer, colon cancer, lymphoma, and hepatocellular carcinoma significantly reduced tumor growth and increased survival in a PMN-MDSC–dependent manner. Loss of Cd300ld also resulted in a TME-wide shift from a protumor to an antitumor phenotype, which was reflected by a depletion of PMN-MDSCs and other myeloid cells as well as increased infiltration of cytotoxic CD8⁺ and CD4⁺ T cells. Evaluation of the function of CD300ld in PMN-MDSCs revealed that Cd300ld depletion hinders PMN-MDSC migration and PMN-MDSC–dependent T-cell suppression. Mechanistically, STAT3-dependent induction of S100A8 and S100A9 mediated the recruitment and migration of PMN-MDSCs and suppression of cytotoxic T cells downstream of CD300ld. Moreover, competitive blockade of CD300ld using its extracellular domain inhibited established tumor growth and impaired neutrophil recruitment, and genetic ablation of Cd300ld showed synergy with anti–PD-1 treatment, suggesting that blocking CD300ld could improve the efficacy of immune checkpoint blockade. Finally, investigation of the role of CD300ld in human samples demonstrated an overexpression in tumor-bearing tissue, with CD300ld signaling also being associated with poor prognosis and enhanced neutrophil infiltration. In summary, this study identified CD300ld on PMN-MDSCs as an immune suppressor that promotes tumor progression and suggests that CD300ld is a promising target for cancer immunotherapy.

Wang C, Zheng X, Zhang J, Jiang X, Wang J, Li Y, et al. CD300ld on neutrophils is required for tumour-driven immune suppression. Nature 2023;621:830–9.

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