SMARCA4-mutant lung cancer disrupts anti-tumor immunity and immunotherapy response in a STING pathway-dependent manner [H1792_RNA-seq]

Genomic studies have identified frequent alterations in components of the SWI/SNF (SWItch/Sucrose Non- Fermenting) chromatin remodeling complex including SMARCA4 and ARID1A. Recent independent clinical studies have shown that SMARCA4 mutant lung cancer patients have very poor response to immunotherapy but the mechanism is unknown. Here we showed that SMARCA4 deficiency caused resistance to anti-PD1 immunotherapy and decreased CD4+ T cell and conventional class I dendritic cells (“cDC1s”) percentage in tumor microenvironment (TME) with mouse models. SMARCA4 loss in tumor cells prevented STING pathway sensing cytosolic DNA and cGAMP to reduce type I IFN and inflammatory cytokine gene expression. Importantly, SMARCA4 degradation induced a profound reprograming of the enhancer landscape with marked loss of chromatin accessibility at enhancers of genes involved in type I IFN and inflammatory cytokine, which is associated with nuclear factor NF-?B pathway. Our finding reveals that SMARCA4 loss can have a critical immune modulatory impact in cancer cell intrinsic fashion and suggest that manipulation of SMARCA4 in tumor cells can improve cancer immunotherapy. Overall design: Total RNA was extracted from H1792 human lung cancer cell line.There are two replicates for each sample.

基因组研究已发现SWI/SNF（SWItch/Sucrose Non-Fermenting，开关/蔗糖非发酵）染色质重塑复合物的组分频发突变，包括SMARCA4与ARID1A。近期多项独立临床研究表明，SMARCA4突变型肺癌患者对免疫治疗的应答效果极差，但其具体机制尚不明确。本研究借助小鼠模型证实，SMARCA4缺陷会引发抗PD-1免疫治疗耐药，并降低肿瘤微环境（TME）中CD4+ T细胞与常规I型树突状细胞（conventional class I dendritic cells，简称cDC1s）的占比。肿瘤细胞内的SMARCA4缺失会阻碍STING通路对胞质DNA与cGAMP的感知，进而降低I型干扰素（type I IFN）及炎性细胞因子的基因表达水平。尤为关键的是，SMARCA4降解会引发增强子景观的显著重编程，使参与I型干扰素与炎性细胞因子合成的基因增强子的染色质可及性大幅降低，这一过程与核因子NF-κB（nuclear factor NF-κB）通路密切相关。本研究结果揭示，SMARCA4缺失可通过癌细胞固有途径对免疫调控产生关键影响，同时提示在肿瘤细胞中调控SMARCA4的表达水平，可有效改善癌症免疫治疗效果。整体实验设计：从H1792人肺癌细胞系中提取总RNA，每个样本设置两个生物学重复。