Abstract B002: HIF-2A inhibition in adaptive immunity against cancer growth

Abstract Hypoxia Inducible Factors (HIFs) are transcription factors implicated in many cellular processes key to survival, proliferation, and function, particularly for cancer cells. HIF2A has been identified as an oncogene in the context of renal cell carcinoma (RCC), and belzutifan (MK-6482) is a HIF2A inhibitor that is FDA-approved for VHL-associated and advanced RCC. HIF1A and HIF2A are expressed by all cells in the hypoxic tumor microenvironment, including anti-tumor immune cells, and have been shown to drive T cell effector function. Several ongoing clinical trials are evaluating MK-6482 in combination with immune checkpoint blockade therapy for advanced RCC, however the potential impact that MK-6482 may directly have on the adaptive immune response remains poorly understood. Considering the functional link between HIF signaling and T cell function, we explored whether HIF-2A inhibition by MK-6482 could impact activation and/or anti-tumor action of T cells supported by anti-PD-1 and anti-CTLA-4 immune checkpoint blockade. Interrogation of primary T cell activation by mixed lymphocyte reaction revealed that MK-6482 did not induce significant changes in cytokine secretion or cell proliferation with or without immune checkpoint blockade, despite evidence of HIF2A protein reduction. MK-6482 in combination with immune checkpoint blockade increased antitumor efficacy compared to either alone in an RCC humanized mouse model, resulting in almost complete tumor regression. IHC analysis of tumors revealed a trend of increased T cell infiltration and a significant reduction in HIF2A protein following combined treatment, potentially contributing to the tumor regression. mRNA sequencing of tumors also revealed increased expression of T cell activation pathways, suggesting that the combination treatment induced greater anti-tumor activity of infiltrating T cells. Together, our data support continued clinical evaluation of belzutifan and checkpoint blockade combination treatment for RCC, and we continue to explore the potential mechanistic effects by both in vivo and in vitro follow-up studies. Citation Format: Katya Frazier, Eric Muise, Joshua Stolz, Lukas Fischer, Mark Buchanan, Charlie Schneider, Brian Pak Ho Chan, Richard Carr, Rodolfo Perini, Brian Long, Douglas Linn. HIF-2A inhibition in adaptive immunity against cancer growth [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B002.