MTA-cooperative PRMT5 inhibitors enhance T cell-mediated antitumor activity in MTAP-loss tumors
Background: Hyperactivated protein arginine methyltransferases (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.  Methods: Isogeneic tumor lines with and without MTAP loss were generated by CRISPR/Cas9 knockout. The effects of two PRMT5 inhibitors (GSK3326595 and MRTX1719) were evaluated in these isogenic tumor lines and T cells in vitro and in vivo. Transcriptomic and proteomic changes in tumors and T cells were characterized in response to PRMT5i treatment.  Results: transcriptomic and proteomic profiling analysis reveals that MRTX1719 successfully reduces activation of the PI3K pathway, a well-documented immune-resistant pathway. It highlights the potential of MRTX1719 to overcome immune resistance in MTAP-loss tumors.  Conclusion: Collectively, our results provide a strong rationale and mechanistic insights for the clinical development of MRTX1719-based IO combinations in MTAP-loss tumors. Overall design: To explore the molecular mechanisms through how PRMT5-dependent tumorigenesis effect on anti-tumor immune response, we generated the following genetically modified MC38/gp100 cell lines and pmel-1 T cells. Samples were in vitro treated by PRMT5is for mechanistic studies.  A1, MC38/gp100 cells control; A2, MC38/gp100 cells treated by 0.5 µM GSK3326595; A4, MC38/gp100 cells treated by 0.5 µM MRTX1719; B1, MC38/gp100 Mtap-KO cells control; B2, MC38/gp100 Mtap-KO cells treated by 0.5 µM GSK3326595; B4, MC38/gp100 Mtap-KO cells treated by 0.5 µM MRTX1719; C1, pmel-1 T cells isolated from transgetic mice, control; C2, pmel-1 T cells isolated from transgetic mice, treated by 0.5 µM GSK3326595; C4, pmel-1 T cells isolated from transgetic mice, treated by 0.5 µM MRTX1719.