Chen Yunqing, Xu Ying, Zhao Miaoxian, Liu Yu, Gong Mingxing, Xie Cantao, Wu Hongkai, Wang Zhanhui
Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University , Guangzhou, China.
State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University , Guangzhou, China.
Oncoimmunology. 2016 Aug 5;5(10):e1219010. doi: 10.1080/2162402X.2016.1219010. eCollection 2016.
T lymphocytes, which recognize antigen peptides through specific T cell receptors (TCRs), play an important role in the human adaptive immune response. TCR diversity is closely associated with host immune response and cancer prognosis. Although tumor-infiltrating T lymphocytes have implications for tumor prognosis, few studies have performed a detailed characterization of TCR diversity in both tumor and non-tumor tissues in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). Here, we performed high-throughput sequencing of the TCRβ chain complementarity determining region 3 (CDR3) of liver-infiltrating T cells from 48 HBV-associated HCC patients. A significantly higher average number of CDR3 aa clonotypes (2259 vs. 1324, < 0.001), and significantly higher TCR diversity (Gini coefficient, < 0.001; Simpson index, < 0.01; Shannon entropy, < 0.001) were observed in tumor tissues compared with adjacent non-tumor tissues. The ratio of highly expanded clones (HECs) was significantly higher in non-tumor tissues than in tumor tissues when the HEC threshold was defined as 2% or greater ( < 0.05). Our analysis of the median Morisita-Horn index indicated weak TCR repertoire similarity between tumor and matched non-tumor tissues. The median number of shared clones in tumor tissue and matched non-tumor tissue from each patient was 360.5, representing 5.1-15.8% (10.6 ± 0.4%) of all clones in each patient. We observed extensive heterogeneity of T lymphocytes in tumors and higher HEC ratios in adjacent non-tumor tissues of HCC patients. The differential T cell repertoires in tumor and non-tumor tissues suggest a distinct T cell immune microenvironment in patients with HBV-associated HCC.
T淋巴细胞通过特异性T细胞受体（TCR）识别抗原肽，在人类适应性免疫反应中发挥重要作用。TCR多样性与宿主免疫反应和癌症预后密切相关。尽管肿瘤浸润性T淋巴细胞对肿瘤预后有影响，但很少有研究对乙型肝炎病毒（HBV）相关肝细胞癌（HCC）的肿瘤组织和非肿瘤组织中的TCR多样性进行详细表征。在此，我们对48例HBV相关HCC患者肝脏浸润性T细胞的TCRβ链互补决定区3（CDR3）进行了高通量测序。与相邻非肿瘤组织相比，肿瘤组织中观察到CDR3氨基酸克隆型的平均数量显著更高（2259对1324，<0.001），且TCR多样性显著更高（基尼系数，<0.001；辛普森指数，<0.01；香农熵，<0.001）。当高扩增克隆（HEC）阈值定义为2%或更高时，非肿瘤组织中的HEC比例显著高于肿瘤组织（<0.05）。我们对中位数森下-霍恩指数的分析表明，肿瘤组织与匹配的非肿瘤组织之间的TCR库相似性较弱。每位患者肿瘤组织和匹配的非肿瘤组织中共享克隆的中位数为360.5，占每位患者所有克隆的5.1-15.8%（10.6±0.4%）。我们观察到HCC患者肿瘤中T淋巴细胞存在广泛异质性，且相邻非肿瘤组织中的HEC比例更高。肿瘤组织和非肿瘤组织中不同的T细胞库表明HBV相关HCC患者存在独特的T细胞免疫微环境。
