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

Djajawi, TM; Pijpers, L; Srivaths, A; Chisanga, D; Chan, KF; Hogg, SJ; Neil, L; Rivera, SM; Bartonicek, N; Ellis, SL; Lim Kam Sian, TCC; Faridi, P; Liao, Y; Pal, B; Behren, A; Shi, W; Vervoort, SJ; Johnstone, RW; Kearney, CJ

Author(s): Djajawi, TM; Pijpers, L; Srivaths, A; Chisanga, D; Chan, KF; Hogg, SJ; Neil, L; Rivera, SM; Bartonicek, N; Ellis, SL; Lim Kam Sian, TCC; Faridi, P; Liao, Y; Pal, B; Behren, A; Shi, W; Vervoort, SJ; Johnstone, RW; Kearney, CJ;
Details: Publication Year 2024-02-23,Volume 43,Issue #3,Page 113831
Journal Title: Cell Reports
Abstract: 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.
Keywords: CP: Cancer; CP: Immunology; Prmt1; Stat1; argenine methylation; cancer; immunology
Research Division(s): Epigenetics And Development
PubMed ID: 38401121
Publisher's Version: https://doi.org/10.1016/j.celrep.2024.113831
Open Access at Publisher's Site: https://doi.org/10.1016/j.celrep.2024.113831
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-02-29 09:16:09

Last Modified: 2024-02-29 09:18:58