ATAC-seq in ARID1A WT or KO OVCA429 Cells after interferron treatment

Whether cancer driver mutation(s) directly drives cancer immune phenotype and immune tolerance remains a standing question. ARID1A is a core member of the polymorphic BAF chromatin remodeling complex. ARID1A mutations frequently occur in human cancers and drive cancer development. Here, we studied the molecular, cellular, and clinical impact of ARID1A gene status on cancer immunity. We demonstrate that ARID1A mutations, limited expression, and deficiency impair interferon(IFN)-responsive gene chromatin accessibility and expression, resulting in anemic T cell tumor infiltration, weakened tumor immunity, and shortened host survival in many human cancer histologies as well as in murine cancer models, and are negatively associated with immunotherapy response. Mechanistically, ARID1A interacts with EZH2 via its carboxyl terminal and antagonizes EZH2-mediated IFN responsiveness. Thus, the interaction between ARID1A and EZH2 defines cancer IFN-responsiveness and immune evasion. Our work indicates that cancer epigenetic driver mutations can shape cancer immune phenotype and immunotherapy. Overall design: OVCA429 WT cells, OVCA429 ARID1A knockout cells were treated with or without IFN? treatment for 3 hours, duplicates

癌症驱动突变是否直接驱动肿瘤免疫表型与免疫耐受，仍是学界悬而未决的核心议题。ARID1A是多态性BAF染色质重塑复合体（BAF chromatin remodeling complex）的核心亚基。ARID1A突变在人类多种肿瘤中频发出现，并可推动肿瘤发生发展。本研究围绕ARID1A基因状态对肿瘤免疫的分子、细胞及临床影响展开系统探究。本研究证实，ARID1A突变、表达下调及功能缺失会损伤干扰素（IFN，interferon）应答基因的染色质开放性与表达水平，进而在多种人类肿瘤组织学类型及小鼠肿瘤模型中引发T细胞肿瘤浸润不足、肿瘤免疫功能减弱以及宿主生存期缩短，且该类改变与免疫治疗应答呈负相关。从机制层面来看，ARID1A可通过其羧基末端与EZH2发生相互作用，并拮抗EZH2介导的干扰素应答通路。综上，ARID1A与EZH2的相互作用决定了肿瘤的干扰素应答能力与免疫逃逸表型。本研究表明，肿瘤表观遗传驱动突变可调控肿瘤免疫表型与免疫治疗应答效果。实验整体设计：将OVCA429野生型（WT，wild type）细胞与OVCA429 ARID1A敲除细胞分别施以干扰素γ（IFNγ）处理与空白对照，处理时长为3小时，每组设置生物学重复（duplicates）。