MTA-Cooperative PRMT5 Inhibitors Enhance T Cell-Mediated Antitumor Activity in MTAP-Loss Tumors

Authors

Si Chen
Jiakai Hou
Roshni Jaffery
Ashley Guerrero
Rongjie Fu
Leilei Shi
Ningbo Zheng
Ritu Bohat
Nicholas A Egan
Chengtai Yu
Sana Sharif
Yue Lu
Wei He
Shuyue Wang
Donjeta Gjuka
Everett M Stone
Pooja Anil Shah
Jordi Rodon Ahnert
Taiping Chen
Xinli Liu
Mark T Bedford
Han Xu
Weiyi Peng

Publication Date

9-23-2024

Journal

Journal of Immunotherapy of Cancer

Abstract

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

RESULTS: GSK3326595 significantly suppresses PRMT5 activity in tumors and T cells regardless of the MTAP status. However, MRTX1719, a methylthioadenosine-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 the 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. In addition, MRTX1719 sensitizes MTAP-loss tumor cells to the killing of tumor-reactive T cells. Combining MRTX1719 and anti-PD-1 leads to superior antitumor activity in mice bearing 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.

Keywords

Animals, Mice, Protein-Arginine N-Methyltransferases, Humans, Purine-Nucleoside Phosphorylase, T-Lymphocytes, Cell Line, Tumor, Female, Neoplasms, Isoquinolines, Pyrimidines, Immunotherapy, Combination therapy

DOI

10.1136/jitc-2024-009600

PMID

39313308

PMCID

PMC11418539

PubMedCentral® Posted Date

9-23-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes