Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3086, Australia.
Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia.
Cell Rep. 2024 Mar 26;43(3):113831. doi: 10.1016/j.celrep.2024.113831. Epub 2024 Feb 23.
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.
癌症免疫疗法已经取得了显著的成功；然而，大多数患者没有反应或产生耐药性。在这里，我们进行了表观遗传学基因靶向 CRISPR-Cas9 筛选，以确定限制 CD8 T 细胞介导的抗肿瘤免疫的表观基因组因素。我们发现 PRMT1 抑制干扰素 γ (Ifnγ) 诱导的 MHC-I 表达，从而抑制 CD8 T 细胞介导的杀伤。事实上，PRMT1 敲除或用临床抑制剂 GSK3368715 靶向 I 型 PRMT，可通过升高 STAT1 表达和激活增强 Ifnγ 诱导的 MHC-I 表达，而在 PRMT1 缺陷细胞中重新引入 PRMT1 则会逆转这种效应。重要的是，PRMT1 的缺失增强了抗 PD-1 免疫疗法的疗效，The Cancer Genome Atlas 分析表明，人类黑色素瘤中 PRMT1 的表达与人类白细胞抗原分子的表达、CD8 T 细胞的浸润和总生存期呈负相关。总之，我们确定 PRMT1 是抗肿瘤免疫的负调节剂，揭示了临床 I 型 PRMT 抑制剂作为免疫治疗剂或作为现有免疫疗法的辅助剂的潜力。
