Abstract Description Hyperactivated PRMTs are implicated in human cancers. Inhibiting tumor intrinsic PRMT5 was reported to potentiate antitumor immune responses, highlighting the possibility of combining PRMT5 inhibitors (PRMT5i) with cancer immunotherapy. However, global suppression of PRMT5 activity impairs 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 in these tumor lines and T cells. Our data show 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, providing a strong rationale for the clinical development of PRMT5i-based IO combinations. Funding Sources Supported in part by the Department of Defense (TC, WP and by Cancer Prevention and Research Institute of Texas (WP, RP200520). Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)
Peng et al. (Sat,) studied this question.
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