PRMT1 acts as a suppressor of MHC-I and anti-tumor immunity

• Published in: Cell reports (Cambridge) Vol. 43; no. 3; p. 113831
• Main Authors: Djajawi, Tirta M., Pijpers, Lizzy, Srivaths, Akash, Chisanga, David, Chan, Kok Fei, Hogg, Simon J., Neil, Liam, Rivera, Sarahi Mendoza, Bartonicek, Nenad, Ellis, Sarah L., Lim Kam Sian, Terry C.C., Faridi, Pouya, Liao, Yang, Pal, Bhupinder, Behren, Andreas, Shi, Wei, Vervoort, Stephin J., Johnstone, Ricky W., Kearney, Conor J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.03.2024; Elsevier
• Subjects: argenine methylation; cancer; CD8-Positive T-Lymphocytes - metabolism; CP: Cancer; CP: Immunology; Histocompatibility Antigens Class I - genetics; Humans; Immunity, Cellular; immunology; Interferon-gamma - metabolism; Melanoma - pathology; PRMT1; Protein-Arginine N-Methyltransferases - genetics; Protein-Arginine N-Methyltransferases - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; STAT1; CP: Immunology; PRMT1; STAT1; CP: Cancer; cancer; immunology; argenine methylation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.113831

Cancer immunotherapies have demonstrated remarkable success; however, the majority of patients do not respond or develop resistance. Here, we conduct epigenetic gene-targeted CRISPR-Cas9 screens to identify epigenomic factors that limit CD8+ T cell-mediated anti-tumor immunity. We identify that PRMT1 suppresses interferon gamma (Ifnγ)-induced MHC-I expression, thus dampening CD8+ T cell-mediated killing. Indeed, PRMT1 knockout or pharmacological targeting of type I PRMT with the clinical inhibitor GSK3368715 enhances Ifnγ-induced MHC-I expression through elevated STAT1 expression and activation, while re-introduction of PRMT1 in PRMT1-deficient cells reverses this effect. Importantly, loss of PRMT1 enhances the efficacy of anti-PD-1 immunotherapy, and The Cancer Genome Atlas analysis reveals that PRMT1 expression in human melanoma is inversely correlated with expression of human leukocyte antigen molecules, infiltration of CD8+ T cells, and overall survival. Taken together, we identify PRMT1 as a negative regulator of anti-tumor immunity, unveiling clinical type I PRMT inhibitors as immunotherapeutic agents or as adjuncts to existing immunotherapies. [Display omitted] •CRISPR screens identify PRMT1 as a negative regulator of tumor cell killing by CD8+ T cells•PRMT1 negatively regulates STAT1-driven MHC-I expression•Loss of PRMT1 augments the efficacy of anti-PD-1 immunotherapy PRMT1 negatively regulates STAT1-driven MHC-I expression and can be targeted to enhance the efficacy of cancer immunotherapy.