Abstract A033: Histone methyltransferase PRMT5 promotes melanoma immune evasion by repressing TH1-related gene networks and endogenous retroelements

Abstract In response to exogenous stimuli, CD4+ T lymphocytes activate lineage-specific, danger-adapted transcriptional networks that dictate their effector functions. These networks are epigenetically modulated by endogenous retroelements, which can affect chromatin organization at T helper (TH) cell-associated genes and enhancer regions. Whether endogenous retroelements can be epigenetically targeted to activate TH1-related gene modules and support cell-mediated immunity remains unexplored. Here, we examined the role of histone methyltransferase PRMT5 in the anti-tumor response to melanoma. We show that genetic or pharmacological inhibition of PRMT5 preferentially enhanced CD4+ TH1 priming, including interferon (IFN)-γ and tumor necrosis factor (TNF)-α production. In preclinical models of immunotherapy-resistant melanoma, targeting PRMT5 synergized with anti-PD-1 treatments to significantly decrease tumor growth in a CD4+ T cell-dependent manner. Spatial deconvolution of the melanoma microenvironment uncovered a significant shift in T cell states caused by PRMT5 blockade, including an accumulation of proliferating, T-bet-expressing CD4+ T cell subsets with progenitor-like features and increased CD8+ cytotoxic T cell activation. These findings were associated with de-repression of discrete retroelements and decreased H3R8me2 epigenetic marks. Finally, transcriptomic analyses of primary human melanoma cell lines from the Yale SPORE program revealed that PRMT5 expression associated with reduced survival and suppressed expression of retroelements and TH1-related cytokine genes. Together, these findings point to PRMT5 as a regulatory, epigenetic hub for retroelements and lineage plasticity in CD4+ T cells and identify a novel approach to augment cell-mediated immunity in melanoma. Citation Format: Simon Milette, Simon F. Roy, Min Hee Oh, Eileen Han, Veronica T. Brooks, Amin Nassar, Tianli Xiao, Walter K. Mowel, Koonam Park, Peili Gu, M. Sam Brickman Raredon, Marcus W. Bosenberg, Richard A. Flavell, Goran Micevic. Histone methyltransferase PRMT5 promotes melanoma immune evasion by repressing TH1-related gene networks and endogenous retroelements [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr A033.