美国索尔克生物研究所Diana C. Hargreaves研究小组发现，ARID1A抑制R-loop介导的STING-type I型干扰素途径激活抗肿瘤免疫。相关论文于2024年5月15日发表于国际顶尖学术期刊《细胞》杂志上。
据了解，临床试验已经鉴定出在几种独立于微卫星不稳定性的实体肿瘤类型中，对免疫检查点阻断(ICB)反应良好的患者中，ARID1A突变富集。
课题组人员发现，小鼠模型中的ARID1A缺失足以诱导在ARID1A突变型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缺失癌症上调干扰素(IFN)基因表达特征，ARID1A-IFN特征与R-loop和细胞单链DNA (ssDNA)增加相关。在ARID1A缺失细胞中，R-loop分解酶RNASEH2B或胞质DNA酶，TREX1的过度表达阻止了胞质单链DNA的积累和ARID1A-IFN基因的上调。
此外，ARID1A-IFN信号和抗肿瘤免疫是由STING依赖的I型IFN信号驱动的，这是改善ARID1A突变肿瘤对ICB治疗的反应性所必需的。这些发现明确了ARID1A突变癌症抗肿瘤免疫的分子机制。
附：英文原文
Title: ARID1A suppresses R-loop-mediated STING-type I interferon pathway activation of anti-tumor immunity
Author: Matthew B. Maxwell, Marianne S. Hom-Tedla, Jawoon Yi, Shitian Li, Samuel A. Rivera, Jingting Yu, Mannix J. Burns, Helen M. McRae, Braden T. Stevenson, Katherine E. Coakley, Josephine Ho, Kameneff Bojorquez Gastelum, Joshua C. Bell, Alexander C. Jones, Ramez N. Eskander, Emily C. Dykhuizen, Gerald S. Shadel, Susan M. Kaech, Diana C. Hargreaves
Issue&Volume: 2024-05-15
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 showthat ARID1A loss in murine models is sufficient to induce anti-tumor immune phenotypesobserved in ARID1A mutant human cancers, including increased CD8+ T cell infiltration and cytolyticactivity. ARID1A-deficient cancers upregulated an interferon (IFN) gene expressionsignature, the ARID1A-IFN signature, associated with increased R-loops and cytosolicsingle-stranded DNA (ssDNA). Overexpression of the R-loop resolving enzyme, RNASEH2B,or cytosolic DNase, TREX1, in ARID1A-deficient cells prevented cytosolic ssDNA accumulationand ARID1A-IFN gene upregulation. Further, the ARID1A-IFN signature and anti-tumorimmunity were driven by STING-dependent type I IFN signaling, which was required forimproved responsiveness of ARID1A mutant tumors to ICB treatment. These findings definea molecular mechanism underlying anti-tumor immunity in ARID1A mutant cancers.
DOI: 10.1016/j.cell.2024.04.025
Source: https://www.cell.com/cell/abstract/S0092-8674(24)00451-3