CRISPR screen reveal that FXYD5 is a potential ligand for Siglec-7 9337

Abstract Description Hypersialylation is a hallmark of cancer cells, modulating immune responses by interacting with Siglecs in the tumor microenvironment. In prostate cancer, Siglec-7 is primarily expressed on macrophages and NK cells. Identifying Siglec-7 ligands is crucial for developing new immune checkpoint inhibitors. Here, we identified FXYD5 as a potential counter-receptor for Siglec-7 by CRISPR screen. FXYD5 expression was significantly higher in androgen receptor (AR)-negative prostate cancer cells compared to AR-positive cells and was expressed in tumor cells from human metastatic prostate cancer tissues. Functional studies revealed that FXYD5 knockout reduced Siglec-7 Fc binding, enhanced NK cell-mediated cytotoxicity, and increased macrophage-mediated phagocytosis. FXYD5 overexpression reduced phagocytosis by macrophages. In a humanized mouse model, 22Rv1 tumor growth was effectively suppressed by immune cell-mediated therapy. However, when FXYD5 was overexpressed in 22Rv1 cells, immune cell-based therapy failed to suppress tumor growth. This resistance was attributed to the interaction of FXYD5 on cancer cells with Siglec-7 on immune cells, triggering immunosuppressive signaling. These findings suggest that the FXYD5-Siglec-7 axis is a key immune evasion mechanism in prostate cancer, presenting a potential therapeutic target for restoring anti-tumor immunity. Funding Sources This work was supported by a Department of Defense (DoD) Young Investigator Award (W81XWH2110195) to RMW, ChEM-H postdoc seed grant to RMW. Peter Michael Foundation and William Randolph Hearst Foundation grants to JDB. NCI grant U01CA226051 to SJP, and JDB. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)