Cell Discovery ( IF 33.5 ) Pub Date : 2020-12-08 , DOI: 10.1038/s41421-020-00214-5 Guohe Song , Yang Shi , Meiying Zhang , Shyamal Goswami , Saifullah Afridi , Lu Meng , Jiaqiang Ma , Yi Chen , Youpei Lin , Juan Zhang , Yuming Liu , Zijie Jin , Shuaixi Yang , Dongning Rao , Shu Zhang , Aiwu Ke , Xiaoying Wang , Ya Cao , Jian Zhou , Jia Fan , Xiaoming Zhang , Ruibin Xi , Qiang Gao
Diverse immune cells in the tumor microenvironment form a complex ecosystem, but our knowledge of their heterogeneity and dynamics within hepatocellular carcinoma (HCC) still remains limited. To assess the plasticity and phenotypes of immune cells within HBV/HCV-related HCC microenvironment at single-cell level, we performed single-cell RNA sequencing on 41,698 immune cells from seven pairs of HBV/HCV-related HCC tumors and non-tumor liver tissues. We combined bio-informatic analyses, flow cytometry, and multiplex immunohistochemistry to assess the heterogeneity of different immune cell subsets in functional characteristics, transcriptional regulation, phenotypic switching, and interactions. We identified 29 immune cell subsets of myeloid cells, NK cells, and lymphocytes with unique transcriptomic profiles in HCC. A highly complex immunological network was shaped by diverse immune cell subsets that can transit among different states and mutually interact. Notably, we identified a subset of M2 macrophage with high expression of CCL18 and transcription factor CREM that was enriched in advanced HCC patients, and potentially participated in tumor progression. We also detected a new subset of activated CD8+ T cells highly expressing XCL1 that correlated with better patient survival rates. Meanwhile, distinct transcriptomic signatures, cytotoxic phenotypes, and evolution trajectory of effector CD8+ T cells from early-stage to advanced HCC were also identified. Our study provides insight into the immune microenvironment in HBV/HCV-related HCC and highlights novel macrophage and T-cell subsets that could be further exploited in future immunotherapy.
中文翻译:
HBV / HCV相关肝细胞癌的全球免疫特征鉴定了与疾病进展相关的巨噬细胞和T细胞亚群
肿瘤微环境中的多种免疫细胞形成一个复杂的生态系统,但是我们对它们在肝细胞癌(HCC)中的异质性和动态的了解仍然有限。为了在单细胞水平上评估HBV / HCV相关HCC微环境中免疫细胞的可塑性和表型,我们对来自7对HBV / HCV相关HCC肿瘤和非肿瘤肝的41,698个免疫细胞进行了单细胞RNA测序组织。我们结合了生物信息学分析,流式细胞仪和多重免疫组织化学,以评估功能特性,转录调控,表型转换和相互作用中不同免疫细胞亚群的异质性。我们确定了HCC中具有独特转录组特征的29个髓样细胞,NK细胞和淋巴细胞的免疫细胞亚群。高度复杂的免疫网络是由可以在不同状态之间迁移并相互作用的多种免疫细胞亚群形成的。值得注意的是,我们鉴定了具有高表达CCL18和转录因子CREM的M2巨噬细胞子集,该子集在晚期HCC患者中富集,并且可能参与了肿瘤的进展。我们还检测到激活的CD8的新子集高表达XCL1的+ T细胞与更好的患者存活率相关。同时,还确定了不同的转录组特征,细胞毒性表型和效应CD8 + T细胞从早期到晚期HCC的进化轨迹。我们的研究为HBV / HCV相关HCC的免疫微环境提供了见识,并重点介绍了可以在未来的免疫治疗中进一步利用的新型巨噬细胞和T细胞亚群。