Zhao Ning, Zhang Zicheng, Wang Qiang, Li Lin, Wei Zichao, Chen Hongyan, Zhou Meng, Liu Zhihua, Su Jianzhong
State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, PR China.
Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, PR China.
EBioMedicine. 2023 Oct;96:104801. doi: 10.1016/j.ebiom.2023.104801. Epub 2023 Sep 17.
DNA damage repair (DDR) is a critical process that maintains genomic integrity and plays essential roles at both the cellular and organismic levels. Here, we aimed to characterize the DDR profiling of esophageal squamous cell carcinoma (ESCC), investigate the prognostic value of DDR-related features, and explore their potential for guiding personalized treatment strategies.
We analyzed bulk and single-cell transcriptomics data from 377 ESCC cases from our institution and other publicly available cohorts to identify major DDR subtypes. The heterogeneity in cellular and functional properties, tumor microenvironment (TME) characteristics, and prognostic significance of these DDR subtypes were investigated using immunogenomic analysis and in vitro experiments. Additionally, we experimentally validated a combinatorial immunotherapy strategy using syngeneic mouse models of ESCC.
DDR alteration profiling enabled us to identify two distinct DDR subtypes, DDR and DDR, which exhibited independent prognostic values in locoregional ESCC but not in metastatic ESCC. The DDR subtype was characterized by an inflamed but immune-suppressed microenvironment with relatively high immune cell infiltration, abnormal immune checkpoint expression, T-cell exhaustion, and enrichment of cancer-related pathways. Moreover, DDR subtyping indicates that BRCA1 and HFM1 are robust and independent prognostic factors in locoregional ESCC. Finally, we proposed and verified that the concomitant triggering of GITR or blockade of BTLA with PD-1 blockade or cisplatin chemotherapy represents effective combination strategies for high-risk locoregional ESCC tumors.
Our discovery of DDR-based molecular subtypes will enhance our understanding of tumor heterogeneity and have significant clinical implications for the therapeutic and management strategies of locoregional ESCC.
This study was supported by the National Key R&D Program of China (2021YFC2501000, 2022YFC3401003), National Natural Science Foundation of China (82172882), the Beijing Natural Science Foundation (7212085), the CAMS Innovation Fund for Medical Sciences (2021-I2M-1-018, 2021-I2M-1-067), the Fundamental Research Funds for the Central Universities (3332021091), and the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2019PT310027).
DNA损伤修复（DDR）是维持基因组完整性的关键过程，在细胞和机体水平上都发挥着重要作用。在此，我们旨在表征食管鳞状细胞癌（ESCC）的DDR谱，研究DDR相关特征的预后价值，并探索其指导个性化治疗策略的潜力。
我们分析了来自本机构的377例ESCC病例以及其他公开可用队列的批量和单细胞转录组学数据，以确定主要的DDR亚型。使用免疫基因组分析和体外实验研究了这些DDR亚型在细胞和功能特性、肿瘤微环境（TME）特征以及预后意义方面的异质性。此外，我们使用ESCC的同基因小鼠模型通过实验验证了一种联合免疫治疗策略。
DDR改变谱使我们能够识别出两种不同的DDR亚型，即DDR和DDR，它们在局部区域ESCC中具有独立的预后价值，但在转移性ESCC中则不然。DDR亚型的特征是炎症但免疫抑制的微环境，具有相对较高的免疫细胞浸润、异常的免疫检查点表达、T细胞耗竭以及癌症相关通路的富集。此外，DDR亚型分类表明，BRCA1和HFM1是局部区域ESCC中强大且独立的预后因素。最后，我们提出并验证了，同时触发GITR或用PD-1阻断或顺铂化疗阻断BTLA是高危局部区域ESCC肿瘤的有效联合策略。
我们基于DDR的分子亚型的发现将增进我们对肿瘤异质性的理解，并对局部区域ESCC的治疗和管理策略具有重要的临床意义。
本研究得到了国家重点研发计划（2021YFC2501000，2022YFC3401003）、国家自然科学基金（82172882）、北京市自然科学基金（7212085）、中国医学科学院医学与健康科技创新工程（2021-I2M-1-018，2021-I2M-1-067）、中央高校基本科研业务费（3332021091）以及中国医学科学院公益性行业科研专项（2019PT310027）的支持。
