PRMT7 Ablation Stimulates Anti-Tumor Immunity and Sensitizes Melanoma to Immune Checkpoint Blockade

Authors

Nivine Srour
Oscar D Villarreal
Swanand Hardikar
Zhenbao Yu
Samuel Preston
Wilson H Miller
Magdelena M Szewczyk
Dalia Barsyte-Lovejoy
Han Xu
Taiping Chen
Sonia V Del Rincón
Stéphane Richard

Publication Date

3-29-2022

Journal

Cell Reports

Abstract

Despite the success of immune checkpoint inhibitor (ICI) therapy for cancer, resistance and relapse are frequent. Combination therapies are expected to enhance response rates and overcome this resistance. Herein, we report that combining PRMT7 inhibition with ICI therapy induces a strong anti-tumor T cell immunity and restrains tumor growth in vivo by increasing immune cell infiltration. PRMT7-deficient B16.F10 melanoma exhibits increased expression of genes in the interferon pathway, antigen presentation, and chemokine signaling. PRMT7 deficiency or inhibition with SGC3027 in B16.F10 melanoma results in reduced DNMT expression, loss of DNA methylation in the regulatory regions of endogenous retroviral elements (ERVs) causing their increased expression. PRMT7-deficient cells increase RIG-I and MDA5 expression with a reduction in the H4R3me2s repressive histone mark at their gene promoters. Our findings identify PRMT7 as a regulatory checkpoint for RIG-I, MDA5, and their ERV-double-stranded RNA (dsRNA) ligands, facilitating immune escape and anti-tumor T cell immunity to restrain tumor growth.

Keywords

Animals, Endogenous Retroviruses, Immune Checkpoint Inhibitors, Interferons, Melanoma, Experimental, Neoplasm Recurrence, Local, PRMT7, arginine methylation, melanoma, immune checkpoint inhibitors, cytotoxic T cells, anti-tumor immunity, dsRNA, RLR pathway, DNMTs

DOI

10.1016/j.celrep.2022.110582

PMID

35354055

PMCID

PMC9838175

PubMedCentral® Posted Date

1-13-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes