Abstract 5613: Targeting VSIG4, a novel macrophage checkpoint, repolarizes suppressive macrophages which induces an inflammatory response in primary cell in vitro assays and fresh human tumor cultures, and inhibits tumor growth in in vivo murine tumor models

Abstract VSIG4 is a B7 family related protein with known roles as a complement receptor involved in pathogen clearance as well as a negative regulator of T cell activation by an undetermined mechanism. VSIG4 is expressed in tumor associated macrophages (TAMs) with exquisite specificity. In cancer, increased expression of VSIG4 has been associated with worse survival in multiple indications, including non-small cell lung cancer, multiple myeloma, ovarian cancer, and glioma, suggesting an important role in tumor immune evasion. Based upon computational analysis of transcript data across thousands of primary cancer and normal tissue samples, we hypothesized that VSIG4 has an important regulatory role in promoting M2-like immune suppressive macrophages in the tumor microenvironment, and that targeting VSIG4 via a monoclonal antibody could relieve VSIG4-mediated macrophage suppression by repolarizing TAMs to an inflammatory phenotype capable of coordinating an anti-tumor immune response. The ability of anti-VSIG4 antibodies to repolarize M2-like macrophages and induce broad immune activation was studied in in vitro, ex vivo, and in vivo models. In in vitro primary cell assays, anti-VSIG4 upregulated pro-inflammatory cytokines and chemokines in M-CSF plus IL-10 driven monocyte-derived M2c macrophages, inducing a shift toward an M1-like phenotype. In a multicellular assay system, blockade of VSIG4 on M2c macrophages co-cultured with autologous T cells in the presence of SEB activation upregulated the expression of both pro-inflammatory myeloid-derived cytokines and T cell-derived cytokines, suggesting that macrophage repolarization in vitro can induce T cell activation. To assess these observations in a relevant translational model, fresh, patient-derived tumor samples were treated ex vivo with anti-VSIG4. Across multiple tumor types, anti-VSIG4 treatment resulted in a significant upregulation of cytokines involved in TAM repolarization and T cell activation, and chemokines involved in immune cell recruitment, at levels generally greater than observed by treatment with anti-PD-1. To determine whether targeting VSIG4 can lead to an anti-tumor effect in vivo, syngeneic mouse models were dosed with anti-mouse VSIG4 antibodies. Tumor growth inhibition was observed in syngeneic mouse models dosed with anti-VSIG4 alone and in combination with anti-PD-1. Tumor growth inhibition was partially reversed in studies where CD8+ T cells were depleted, demonstrating that targeting VSIG4 on macrophages can elicit a coordinated attack on tumors in vivo through both innate and adaptive immune responses. Taken together, these data suggest that VSIG4 represents a promising new target capable of stimulating an anti-cancer response via multiple key immune mechanisms. Citation Format: Stephen Sazinsky, Ani Nguyen, Mohammad Zafari, Boris Klebanov, Jessica Ritter, Veronica Komoroski, Denise Manfra, Igor Feldman, Tatiana Novobrantseva. Targeting VSIG4, a novel macrophage checkpoint, repolarizes suppressive macrophages which induces an inflammatory response in primary cell in vitro assays and fresh human tumor cultures, and inhibits tumor growth in in vivo murine tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5613.