Inhibitors of protein arginine methyltransferases (PRMTs) are being developed as cancer therapeutics. Srour et al. identified an association between high levels of one PRMT (PRMT7) and reduced survival in patients with melanoma. They used the B16.F10 melanoma model to examine the role of PRMT7 in antitumoral immunity. KO of PMRT7 rendered B16.F10 cells more susceptible to checkpoint inhibitors, and treatment with PRMT7 inhibitors reduced B16.F10 growth and increased survival. PRMT7 was shown to negatively regulate activation of IFNγ pathways, antigen presentation, and chemokine signaling through epigenetic inhibition of the RLR pathway.
Contributed by Margot O’Toole
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.
Author Info: (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, C
Author Info: (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; 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. (5) Segal Cancer Center, Lady Davis Institute for Medical Research, Montréal, QC H3T 1E2, Canada; Department of Medicine, McGill University, Montréal, QC H3A 1A1, Canada. (6) 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. (7) Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada. (8) Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada. (9) Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (10) Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (11) 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. (12) 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.
