卵巢癌是女性生殖系统最常见的恶性肿瘤，预后极差。肿瘤免疫检测点阻断（ICB）在卵巢癌中效果不佳，主要原因是卵巢癌突变负荷低。申请者前期发现 BRD4 拷贝数扩增是卵巢癌最重要的分子特征之一，因此 BRD4 抑制剂（BRD4i）将是卵巢癌治疗非常有前景的靶向药物；同时BRD4i可通过下调MSH6导致错配修复缺陷（dMMR），而dMMR是目前ICB 敏感性的最佳预测指标。本研究拟通过体内外实验阐明BRD4调控MSH6 的具体机制，并将通过WES，RNA-Seq动态计算BRD4i治疗后对肿瘤新生抗原、免疫原性的影响，以及利用鼠源性卵巢癌体内模型、T细胞单细胞测序和TCR 测序分析、以及患者来源的肿瘤类器官微球体（PDOTS）模型进行临床验证，探讨BRD4i 与ICB续贯/联合治疗卵巢癌的有效性和实用性，完成本项目不仅具有理论意义，而且对为卵巢癌的治疗提供一个新的方向。

Ovarian cancer is the most common malignant tumor in the female reproductive system with a very poor prognosis. The response rates of immune checkpoint blockage (ICB) in ovarian cancer is extremely low, mainly due to the low tumor mutation burden (TMB) of ovarian cancer. We have previously found that BRD4 amplification is one of the most important molecular features of ovarian cancer, so BRD4 inhibitor (BRD4i) will be a very promising targeted drug for ovarian cancer treatment. Moreover, while mismatch repair deficiency (dMMR) is the best biomarker for the sensitivity of ICB, we found BRD4i induce dMMR by down-regulating MSH6. First, we intend to demonstrate the mechanism of BRD4 regulating MSH6 by in vitro and in vivo models. Then, we plan to test the effect of BRD4i on tumor neoantigen and immunogenicity by dynamically analyzing WES, RNA-Seq data. Third, we will test the efficacy of anti-PD-L1 in BRD4i treated/resistant murine ovarian cancer cells compared to parental cells in vivo, and we will apply T cell single-cell sequencing and TCR sequencing in tumor infiltrated T cells to validate the enhanced immunogenicity after BRD4i treatment. Finally, we will explore the possibility of sequential treatment with BRD4i and ICB (anti-PDL1) in patient-derived organotypic tumor microsphere (PDOTS) model of ovarian cancer. So, the completion of this project is not only of theoretical significance but also provide a novel direction for ovarian cancer treatment.