Abstract A067: PRMT7 deficiency in T cells enhances immune response and fosters an anti-tumor microenvironment in melanoma

Abstract Exploration in the field of epigenetics has unveiled the significance of protein arginine methyltransferases (PRMTs) in normal development and disease. Our research identified PRMT7 as a promising target for enhancing the efficacy of cancer immunotherapy in melanoma (Srour et al., 2022, Cell Reports 38(13):110582). To investigate if PRMT7 plays a role in the tumor microenvironment especially in tumor infiltrating lymphocytes (TILs), we bred PRMT7FL/FL mice with CD4-Cre mice (CKO) to generate PRMT7 deficient T cells. PRMT7 CKO mice exhibited a substantial increase in peripheral CD8+ but not CD4+ T cells. These CD8+ T cells had an enhanced T cell effector memory-like phenotype as assessed by CD44, CD62L expression. Interestingly, PRMT7 CKO mice exhibited reduced melanoma growth following subcutaneous injection of B16.F10 cells. Ex vivo stimulation of PRMT7 CKO CD8+ T cells with αCD3 and αCD28 resulted in enhanced proliferation compared to control CD8+ T cells. To replicate PRMT7 depletion observed in the CKO model, we developed novel VHL-ligand coupled PROTAC inhibitors targeting PRMT7. Notably, PRMT7-deficient CD8+ T cells, whether derived from CKO mice or wild-type mice treated with PRMT7 PROTACs, exhibited enhanced cytotoxic activity against melanoma cells in vitro. Furthermore, our data show that adoptive cell transfer (ACT) with PRMT7-deficient OT-I T cells improves tumor control, while ACT with wild-type OT-I effectors has a smaller effect. Transcriptomic analysis of PRMT7-deficient CD8+ T cells revealed multiple alternative splicing defects, along with upregulation of genes related to the NF-κB pathway. Our findings highlight a crucial role for PRMT7 in regulating CD8+ T cell function, reinforcing the need to therapeutically target PRMT7 for adoptive T cell immunotherapies and CAR T cell treatments. Citation Format: Nivine Srour, Yan Xiong, Zhenbao Yu, Theodore Papadopoulos, Kaixiu Luo, François Santinon, Dalia Barsyte-Lovejoy, Sonia Victoria delRincon, Jin Jian, Stéphane Richard. PRMT7 deficiency in T cells enhances immune response and fosters an anti-tumor microenvironment in melanoma [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A067.