Abstract P49: Target PRMTs to Overcome Cancer Immune Resistance

Abstract

Hyperactivated protein arginine methyltransferases (PRMTs) are implicated in human cancers. Genetic screens and other preclinical studies reveal tumor intrinsic PRMTs can suppress T-cell mediated antitumor immune responses, highlighting the possibility of combining PRMT inhibitors (PRMTi) with cancer immunotherapy. However, global suppression of PRMT activity is expected to impair the effector functions of immune cells. Here, we sought to identify strategies to specifically inhibit PRMT5 activity in tumor tissues and develop effective PRMT5i-based immuno-oncology (IO) combinations for cancer treatment, particularly for methylthioadenosine phosphorylase (MTAP)-loss cancer. We generated a set of isogeneic tumor lines with and without MTAP loss, and evaluated the effects of two PRMT5 inhibitors (GSK3326595 and MRTX1719) in these isogenic tumor lines and T cells in vitro and in vivo. We found that GSK3326595 significantly suppresses PRMT5 activity in tumors and T cells regardless of MTAP status. However, MRTX1719, a methylthioadenosine (MTA)-cooperative PRMT5 inhibitor, exhibits tumor-specific PRMT5 inhibition in MTAP-loss tumors with limited immunosuppressive effects. Mechanistically, transcriptomic and proteomic profiling analysis reveals that MRTX1719 successfully reduces activation of the PI3K pathway, a well-documented immune-resistant pathway. Furthermore, the combination of MRTX1719 in combination with immune checkpoint blockade (ICB) leads to superior antitumor activity in two syngeneic murine models with MTAP-loss tumor. Collectively, our results provide a strong rationale for the clinical development of PRMT5i-based IO combinations.