Inhibiting Type I Arginine Methyltransferase Activity Promotes T Cell-Mediated Antitumor Immune Responses

Authors

Andrew Fedoriw
Leilei Shi
Shane O'Brien
Kimberly N Smitheman
Yunfei Wang
Jiakai Hou
Christian Sherk
Satyajit Rajapurkar
Jenny Laraio
Leila J Williams
Chunyu Xu
Guangchun Han
Qin Feng
Mark T Bedford
Linghua Wang
Olena Barbash
Ryan G Kruger
Patrick Hwu
Helai P Mohammad
Weiyi Peng

Publication Date

4-1-2022

Journal

Cancer Immunology Research

Abstract

Protein arginine methyltransferases (PRMT) are a widely expressed class of enzymes responsible for catalyzing arginine methylation on numerous protein substrates. Among them, type I PRMTs are responsible for generating asymmetric dimethylarginine. By controlling multiple basic cellular processes, such as DNA damage responses, transcriptional regulation, and mRNA splicing, type I PRMTs contribute to cancer initiation and progression. A type I PRMT inhibitor, GSK3368715, has been developed and has entered clinical trials for solid and hematologic malignancies. Although type I PRMTs have been reported to play roles in modulating immune cell function, the immunologic role of tumor-intrinsic pathways controlled by type I PRMTs remains uncharacterized. Here, our The Cancer Genome Atlas dataset analysis revealed that expression of type I PRMTs associated with poor clinical response and decreased immune infiltration in patients with melanoma. In cancer cell lines, inhibition of type I PRMTs induced an IFN gene signature, amplified responses to IFN and innate immune signaling, and decreased expression of the immunosuppressive cytokine VEGF. In immunocompetent mouse tumor models, including a model of T-cell exclusion that represents a common mechanism of anti-programmed cell death protein 1 (PD-1) resistance in humans, type I PRMT inhibition increased T-cell infiltration, produced durable responses dependent on CD8+ T cells, and enhanced efficacy of anti-PD-1 therapy. These data indicate that type I PRMT inhibition exhibits immunomodulatory properties and synergizes with immune checkpoint blockade (ICB) to induce durable antitumor responses in a T cell-dependent manner, suggesting that type I PRMT inhibition can potentiate an antitumor immunity in refractory settings.

Keywords

Animals, Arginine, Humans, Immunity, Intracellular Signaling Peptides and Proteins, Mice, Protein-Arginine N-Methyltransferases

DOI

10.1158/2326-6066.CIR-21-0614

PMID

35181787

PMCID

PMC8976792

PubMedCentral® Posted Date

10-1-2022

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes