Shi Xuebing, Li Zhixuan, Yao Renqi, Cheng Qingbao, Li Wei, Wu Rui, Xie Zhihua, Zhu Yanjing, Qiu Xinyao, Yang Shuai, Zhou Tao, Hu Ji, Zhang Yangqianwen, Wu Tong, Zhao Yan, Zhang Yani, Wu Jianmin, Wang Hongyang, Jiang Xiaoqing, Chen Lei
Department I of Biliary Tract, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China.
The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
NPJ Precis Oncol. 2022 Aug 18;6(1):58. doi: 10.1038/s41698-022-00300-9.
Immunotherapies have been explored in treating solid tumors, albeit with disparate clinical effects in distinct cancer types. Systematic interrogation of immune cells in the tumor microenvironment (TME) is vital to the prediction of immunotherapy response and the development of innovative immunotherapeutics. To comprehensively characterize the immune microenvironment in advanced biliary tract cancer (BTC), we utilized single-cell RNA sequencing in unselected viable cells from 16 matched samples, and identified nineteen cell subsets from a total of 45,851 cells, in which exhausted CD8 T cells, macrophages, and dendritic cells (DCs) in BTC were shown to augment and communicate within the TME. Transcriptional profiles coupled with T cell receptor (TCR) sequences revealed that exhausted CD8 T cells retained clonal expansion and high proliferation in the TME, and some of them highly expressed the endoplasmic reticulum stress (ER) response gene, XBP1, indicating the role of ER stress in remodeling TME. Functional assays demonstrated that XBP1 and common immune checkpoints (PD1, TIGIT) were significantly upregulated in CD8 T cells cocultured within the TME of BTC cells (GBC-SD, HCCC-9810). When treating the coculture groups with the specific inhibitor of IRE1α-XBP1 (4μ8C), the downregulation of TIGIT was observed in the treatment group. Collectively, comprehensive transcriptome profiling provides deep insights into the immune atlas in advanced BTC, which might be instrumental in exploring innovative immunotherapy strategies.
免疫疗法已被用于实体瘤治疗，尽管在不同癌症类型中临床效果各异。系统研究肿瘤微环境（TME）中的免疫细胞对于预测免疫治疗反应和开发创新免疫疗法至关重要。为全面表征晚期胆管癌（BTC）的免疫微环境，我们对16对匹配样本中的未分选活细胞进行了单细胞RNA测序，从总共45,851个细胞中鉴定出19个细胞亚群，其中BTC中的耗竭CD8 T细胞、巨噬细胞和树突状细胞（DC）在TME中显示出增加并相互交流。转录谱与T细胞受体（TCR）序列相结合表明，耗竭CD8 T细胞在TME中保留克隆扩增和高增殖能力，其中一些细胞高表达内质网应激（ER）反应基因XBP1，表明ER应激在重塑TME中的作用。功能测定表明，在与BTC细胞（GBC-SD、HCCC-9810）的TME中共培养的CD8 T细胞中，XBP1和常见免疫检查点（PD1、TIGIT）显著上调。用IRE1α-XBP1的特异性抑制剂（4μ8C）处理共培养组时，治疗组中观察到TIGIT下调。总的来说，全面的转录组分析为晚期BTC的免疫图谱提供了深入见解，这可能有助于探索创新免疫治疗策略。
