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Abstract 3268: Anti-tumor effect of VSIG4 in conversion of immunosuppressive type II macrophageviarepolarization

V-set and immunoglobulin domain-containing 4 (VSIG4) is a B7 family-related protein which includes PDL1, VISTA and CTLA4 ligand. The known functions of VSIG4 are a receptor for complement iC3b and C3b to inhibit complement activity and negative regulation of proliferating T cell. Although VSIG4 is highly expressed in tissue-resident macrophage and tumor-associated macrophage (TAM), the mechanism of the signal transduction is not fully elucidated. Here we investigate the pivotal roles of anti-VSIG4 therapeutic antibody in TAM and tumor microenvironment. Anti-VSIG4 antibody engagement altered a broad range of type II macrophage (M2) transcriptome which related to immune-tolerance and increased the proliferation of cytotoxic CD8+T cells. Anti-VSIG4 antibody induced phosphorylation of JNK and p38MAPK and in consequence, decreased the expression of M2 marker CD14, CSF-1R and CD163 while type I macrophage (M1) marker CD86 and CD40 were increased. Furthermore, anti-VSIG4 antibody treatment to TAM in ovarian cancer patients, results in secretion of inflammatory cytokines and chemokines in a similar way to M1 macrophages. In the CD34+-based humanized mouse model, stimulation of VSIG4 attenuated tumor growth and promoted infiltration of IFN-gamma-producing CD8+ T cells into tumor tissue. Adopted transfer of differentiated M2 macrophages to immune-deficient NSG mice confirmed M2 conversion into M1 macrophage phenotype with anti-VSIG4 antibody. Our finding suggests that anti-VSIG4 antibody directly act on TAM and induce repolarization of TAM to tumor suppressive M1 macrophages, leading to a CD8+ T cell proliferation and tumor suppression. Overall, targeting the VSIG4 would be an advantageous candidate in cancer therapeutics. Citation Format: Hye Jeong Kim, Sunhee Hwang, Seung-Hyun Lee, HyunTae Son, Joong Won Lee, Byoung S. Kwon. Anti-tumor effect of VSIG4 in conversion of immunosuppressive type II macrophage via repolarization [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3268.