CD244 loss on monocytes promotes differentiation into M1 macrophages and potentiates PD-L1 blockade in melanoma

Abstract Accumulating data have highlighted the role of monocytes/macrophages in immune escape by generating immunologically “cold” tumors that do not respond to immunotherapy. CD244 (SLAMF4, 2B4), a member signaling lymphocyte activation molecule family, is expressed on myeloid cells, but its precise has been elucidated. Using monocyte lineage-specific CD244-deficient micechallenged with B16F10 melanoma, we report for first time negatively regulates tumor immunity inhibiting differentiation and functional maturation monocytes into macrophageswithin microenvironment. macrophages more effectively activated antigen-specific T cell responsescompared WT macrophages, thus delaying growth melanoma model. Moreover, combinatorial intervention anti-PD-L1 antibodies CD244-KO BMDM markedly improved rejectioncompared antibody alone or combination BMDM. Consistent murine data, transcriptome analysis human tissue single-cell RNA-sequencing dataset, revealed DEGs −monocytes were associated phagocytosis, antigen presentation, autophagy. Additionally, type deconvolution within patients bulk RNA-seq datasets from TCGA database, presence CD244-monocytes/macrophages significantly increased patient survival primary metastatic tumors. Hence, proposed serve as critical immunoregulatory receptor may represent novel therapeutic modality, which can function synergistically checkpoint blockade therapies. Supported grants National Research Foundation Korea (NRF-2020R1A2C2103061, NRF-2018M3A9D3079288, NRF-2016M3A9B6948342)