PDF(Pubmed)
Abstract：
Clinical trials have identified ARID1A mutations as enriched among patients who respond favorably to immune checkpoint blockade (ICB) in several solid tumor types independent of microsatellite instability. We show that ARID1A loss in murine models is sufficient to induce anti-tumor immune phenotypes observed in ARID1A mutant human cancers, including increased CD8+ T cell infiltration and cytolytic activity. ARID1A-deficient cancers upregulated an interferon (IFN) gene expression signature, the ARID1A-IFN signature, associated with increased R-loops and cytosolic single-stranded DNA (ssDNA). Overexpression of the R-loop resolving enzyme, RNASEH2B, or cytosolic DNase, TREX1, in ARID1A-deficient cells prevented cytosolic ssDNA accumulation and ARID1A-IFN gene upregulation. Further, the ARID1A-IFN signature and anti-tumor immunity were driven by STING-dependent type I IFN signaling, which was required for improved responsiveness of ARID1A mutant tumors to ICB treatment. These findings define a molecular mechanism underlying anti-tumor immunity in ARID1A mutant cancers.
摘要：
临床试验已确定ARID1A突变在几种实体瘤类型中对免疫检查点阻断（ICB）反应良好的患者中富集，而与微卫星不稳定性无关。我们表明，小鼠模型中的ARID1A丢失足以诱导在ARID1A突变人类癌症中观察到的抗肿瘤免疫表型，包括CD8+T细胞浸润和细胞溶解活性增加。ARID1A缺陷型癌症上调干扰素（IFN）基因表达特征，ARID1A-IFN签名，与增加的R环和胞浆单链DNA（ssDNA）相关。R-环分解酶的过表达，RNASEH2B,或胞质DNA酶，在ARID1A缺陷型细胞中，TREX1阻止了胞质ssDNA积累和ARID1A-IFN基因上调。Further,ARID1A-IFN标签和抗肿瘤免疫由STING依赖性I型IFN信号驱动，这对于提高ARID1A突变肿瘤对ICB治疗的反应性是必需的。这些发现定义了ARID1A突变癌症中抗肿瘤免疫的分子机制。
