Abstract 2246: VISTA-induced tumor suppression and immunosuppression by shared cell-intrinsic mechanisms

Abstract VISTA is a key immune checkpoint receptor under investigation for cancer immunotherapy; however, its signaling mechanisms remain unclear. Here we identify a four amino acid (NPGF) intracellular motif in VISTA that suppresses cell proliferation by constraining cell-intrinsic growth receptor signaling. The NPGF motif binds to the adapter protein NUMB and recruits Rab11 endosomal recycling machinery. In tumor cells with high VISTA levels, the NPGF motif sequesters NUMB at endosomes, which interferes with epidermal growth factor receptor (EGFR) trafficking and signaling to suppress tumor growth, even without a functioning immune system. To understand if similar principles underlie VISTA-mediated immunosuppression we engineered mice with targeted mutations in the VISTA NPGF motif. These animals had increased T cell signaling and proliferation leading to improved control of tumor growth. These results define a generalizable mechanism by which VISTA represses NUMB to control cell signaling across disparate cell types that could be exploited for immunotherapies. Citation Format: Yan Zhao, Tina Andoh, Ishrat Durdana, Joshua Gruber. VISTA-induced tumor suppression and immunosuppression by shared cell-intrinsic mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2246.