Abstract PR-04: Targeting PRMT5 to modulate endogenous retroviruses expression in melanoma

Abstract Immune checkpoint blockade (ICB) is a mainstay of advanced melanoma treatment but often fails as a consequence of low tumor antigenicity and inadequate immune cell infiltration. Endogenous retroviruses (ERVs) are genomic proviral elements that are epigenetically repressed, in part, through histone modification. ERV re-activation can promote type I interferon (IFN) production and stimulate adaptive responses, which can increase tumor immunogenicity. However, therapeutic efforts to de-repress ERV expression have been hindered by a lack of clinical-grade epigenetic modulators. Protein arginine methyl transferase PRMT5 is a known epigenetic regulator of histone codes with selective and potent inhibitors. Recently, PRMT5 was implicated in the control of the cGAS/STING pathway, which senses cytosolic dsDNA proviral elements. Yet, it remains unclear whether PRMT5 can directly regulate ERV expression through histone methylation and whether it can be targeted to trigger cGAS/STING-IFN responses to augment anti-tumor immunity in melanoma. Here, we show that PRMT5 inhibition alone triggers type I IFN signaling in melanoma, which is mechanistically dependent on STING activity. In a syngeneic preclinical model of melanoma (YUMMER), PRMT5 inhibition acts synergistically with PD-1 blockade to markedly decrease cancer progression in a type I IFN-dependent manner. Spectral flow cytometric deconvolution of the melanoma immune landscape uncovered a significant shift in the lymphoid compartment linked to PRMT5 blockade, including an accumulation of a distinct CD4+PD-1+ICOShi T cell subset and changes to CD8+ T cell states. Importantly, in a syngeneic model of ICB-unresponsive melanoma, we show that PRMT5 inhibition synergizes with ICB to significantly impair tumor expansion in a type I IFN- and CD4+ T cell-mediated fashion. Finally, genomic analyses of primary human melanoma cell lines from the Yale SPORE program reveal that PRMT5 correlates with suppressed expression of discrete ERVs and IFN-stimulated response genes. Together, these findings point to PRMT5 as a direct regulator of ERV expression in melanoma and identify a novel epigenetic approach to augment adaptive anti-tumor immunity. Citation Format: Simon Milette, Simon F. Roy, Veronica T. Brooks, Koonam Parks, Marcus W. Bosenberg, Richard A. Flavell, Goran Micevic. Targeting PRMT5 to modulate endogenous retroviruses expression in melanoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Mechanisms of Cancer Immunity and Cancer-related Autoimmunity; 2025 Sep 24-27; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(9 Suppl):Abstract nr PR-04.