Immunogenicity of BRCA1-deficient Ovarian Cancers is Driven through DNA Sensing and is Augmented by PARP Inhibition (Hi-C)

We investigated BRCA1-deficient ovarian cancer to understand why homologous recombination deficiency (HRD) is associated with tumor T-cell inflammation. In humans and mice, BRCA1 deficiency led to increased cytoplasmic translocation of nuclear DNA, increased DNA sensing, induction of proinflammatory cytokines and T-cell recruiting chemokines, and increased tumor CD8+ T-cell infiltration. This cascade was mediated by STING and phosphorylation of TBK1, IRF3 and STAT1. BRCA1 loss activated a transcriptional reprogramming of tumor cells, leading to overexpression of the DNA sensing pathway and hyper-responsiveness to cytoplasmic DNA. Genetic alterations of the DNA sensing and interferon pathways modulated the impact of HRD on T-cell inflammation. PARP inhibitor olaparib exacerbated cytoplasmic DNA and the cell-autonomous inflammatory activation of BRCA1-deficient cancers, and rendered them susceptible to PD-1/CTLA-4 blockade. We conclude that HRD and DNA sensing drives the immunogenicity of ovarian carcinomas and predisposes them to immune vulnerability under immune checkpoint blockade. The human ovarian cancer cell line UWB1.289,which harbors a deleterious mutation in BRCA1 exon11 and LOH, was profiled its chromatin structure by HiC. Same experimental procedure was followed for UWB1.289 BRCA1 wt reconstituted isogenic pair.

本研究针对BRCA1缺陷型卵巢癌开展探究，旨在阐明同源重组缺陷（homologous recombination deficiency, HRD）与肿瘤T细胞炎症之间的关联机制。在人类及小鼠模型中，BRCA1缺陷可促使细胞核DNA向细胞质的移位水平升高，增强DNA传感通路激活，诱导促炎细胞因子及T细胞趋化因子的转录表达，并提升肿瘤组织中CD8+T细胞的浸润水平。该信号级联反应由STING介导，并伴随TBK1、IRF3及STAT1的磷酸化修饰。BRCA1缺失会触发肿瘤细胞的转录重编程，使得DNA传感通路相关基因过度表达，同时增强肿瘤细胞对细胞质DNA的高应答性。DNA传感与干扰素通路的遗传变异，可调控HRD对T细胞炎症的影响效应。PARP抑制剂奥拉帕利（olaparib）会进一步加剧BRCA1缺陷型癌细胞的细胞质DNA积累与细胞自主性炎症激活，使其对PD-1/CTLA-4免疫检查点阻断治疗产生敏感性。综上，本研究证实HRD与DNA传感通路可驱动卵巢癌的免疫原性，并使得肿瘤在免疫检查点阻断治疗下呈现免疫易感性。本研究通过HiC技术，对携带BRCA1外显子11有害突变及杂合性缺失（Loss of Heterozygosity, LOH）的人卵巢癌细胞系UWB1.289开展了染色质结构谱分析。对于经BRCA1野生型（wild type, wt）重构的同基因UWB1.289细胞系，本研究采用了相同的实验流程进行分析。