PRMT7 ablation stimulates anti-tumor immunity and sensitizes melanoma to immune checkpoint blockade

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

doi:10.1016/j.celrep.2022.110582

PRMT7 ablation stimulates anti-tumor immunity and sensitizes melanoma to immune checkpoint blockade

Cell Rep. 2022 Mar 29;38(13):110582. doi: 10.1016/j.celrep.2022.110582.

Authors

Affiliations

¹ Segal Cancer Center, Lady Davis Institute for Medical Research, Montréal, QC H3T 1E2, Canada; Gerald Bronfman Department of Oncology, McGill University, Montréal, QC H3A 1G5, Canada; Department of Medicine, McGill University, Montréal, QC H3A 1A1, Canada; Department of Human Genetics, McGill University, Montréal, QC H3A 0C7, Canada; Department of Biochemistry, McGill University, Montréal, QC H3A 1A3, Canada.
² Segal Cancer Center, Lady Davis Institute for Medical Research, Montréal, QC H3T 1E2, Canada; Gerald Bronfman Department of Oncology, McGill University, Montréal, QC H3A 1G5, Canada; Department of Medicine, McGill University, Montréal, QC H3A 1A1, Canada; Department of Human Genetics, McGill University, Montréal, QC H3A 0C7, Canada; Department of Biochemistry, McGill University, Montréal, QC H3A 1A3, Canada; Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
³ Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁴ Segal Cancer Center, Lady Davis Institute for Medical Research, Montréal, QC H3T 1E2, Canada; Department of Medicine, McGill University, Montréal, QC H3A 1A1, Canada.
⁵ Segal Cancer Center, Lady Davis Institute for Medical Research, Montréal, QC H3T 1E2, Canada; Gerald Bronfman Department of Oncology, McGill University, Montréal, QC H3A 1G5, Canada; Department of Medicine, McGill University, Montréal, QC H3A 1A1, Canada.
⁶ Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.
⁷ Segal Cancer Center, Lady Davis Institute for Medical Research, Montréal, QC H3T 1E2, Canada; Gerald Bronfman Department of Oncology, McGill University, Montréal, QC H3A 1G5, Canada; Department of Medicine, McGill University, Montréal, QC H3A 1A1, Canada; Department of Human Genetics, McGill University, Montréal, QC H3A 0C7, Canada; Department of Biochemistry, McGill University, Montréal, QC H3A 1A3, Canada. Electronic address: stephane.richard@mcgill.ca.

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: CP: Cancer; CP: Immunology; DNMTs; PRMT7; RLR pathway; arginine methylation; cytotoxic T cells; dsRNA; immune checkpoint inhibitors; melanoma.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Endogenous Retroviruses*
Immune Checkpoint Inhibitors / pharmacology
Immune Checkpoint Inhibitors / therapeutic use
Interferons / genetics
Melanoma, Experimental* / genetics
Neoplasm Recurrence, Local / genetics

Substances

Immune Checkpoint Inhibitors
Interferons

Abstract

Publication types

MeSH terms

Substances

Grants and funding