Abstract 3232: Developing PRMT5 inhibition-based Immuno-oncology combination therapies in MTAP-loss tumors

Abstract Hyperactivated protein arginine methyltransferases (PRMTs) are implicated in human cancers. Inhibiting tumor-intrinsic PRMT5 has been shown to enhance antitumor immune responses, suggesting the potential of combining PRMT5 inhibitors (PRMT5i) with immunotherapy. However, global PRMT5 inhibition can impair immune cells functions. This study aims to identify strategies for tumor-specific PRMT5 inhibition and PRMT5i-based immuno-oncology (IO) combinations, especially for methylthioadenosine phosphorylase (MTAP)-loss cancers. Isogeneic tumor lines with and without MTAP loss were generated using CRISPR/Cas9 knockout. MTAP inactivation was confirmed by methylthioadenosine (MTA) accumulation and reduced symmetric dimethylarginine levels in MTAP-KO cell lines. Two PRMT5 inhibitors, GSK3326595 (substrate-competitive) and MRTX1719 (MTA-cooperative), were evaluated on tumor and immune cells. As shown in the Table 1, GSK3326595 suppressed PRMT5 activity and cell proliferation in both tumors and immune cells, regardless of MTAP status. Conversely, MRTX1719 selectively inhibited PRMT5 in MTAP-loss tumors, while treated T cells retained cytokine production and cytotoxicity. Transcriptomic and proteomic analyses revealed that MRTX1719 reduced PI3K pathway activation, a well-characterized immune resistant mechanism. In MTAP-loss syngeneic murine models, MRTX1719 combined with anti-PD-1 slowed tumor growth and extended survival (e.g., MC38/gp100 MTAP-KO tumor day 21: Ctrl 95.82±8.87 mm2, PRMT5i 99.99±6.34 mm2, anti-PD-1 94.47±6.76 mm2, combination 72.81±4.14 mm2; B16 MTAP-KO tumor day 18: Ctrl 108.24±9.13 mm2, PRMT5i 106.45±22.54 mm2, anti-PD-1 92.72±28.07 mm2, combination 47.97±22.23 mm2). The combination also increased CD8+ T cell proliferation in MTAP-KO tumor tissues. Collectively, our results provide a strong rationale for the clinical development of MRTX1719-based IO combinations in MTAP-loss tumors. Citation Format: Si Chen. Developing PRMT5 inhibition-based Immuno-oncology combination therapies in MTAP-loss tumors [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 3232.