The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences/University of Chinese Academy of Sciences, Shanghai, 200031, China.
Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
J Immunother Cancer. 2019 Nov 29;7(1):331. doi: 10.1186/s40425-019-0814-7.
BACKGROUND: CD8 T cells differentiate into exhausted status within tumors, including hepatocellular carcinoma (HCC), which constitutes a solid barrier to effective anti-tumor immunity. A detailed characterization of exhausted T cells and their prognostic value in HCC is lacking. METHODS: We collected fresh tumor tissues with adjacent non-tumor liver tissues and blood specimens of 56 HCC patients, as well as archived samples from two independent cohorts of HCC patients (n = 358 and n = 254), who underwent surgical resection. Flow cytometry and multiplex immunostaining were used to characterize CD8 T cells. Patient prognosis was evaluated by Kaplan-Meier analysis and Cox regression analysis. RESULTS: CD8 T cells were classified into three distinct subpopulations: PD1, PD1 and PD1. PD1 CD8 T cells were significantly enriched in tumor compared to adjacent non-tumor liver tissues. PD1 CD8 T cells highly expressed exhaustion-related inhibitory receptors (TIM3, CTLA-4, etc.) and transcription factors (Eomes, BATF, etc.). In addition, PD1 CD8 T cells expressed low levels of cytotoxic molecules and displayed a compromised capacity to produce pro-inflammatory cytokines while the expression of anti-inflammatory IL-10 was up-regulated following mitotic stimulation. Furthermore, PD1 CD8 T cells shared features with tissue resident memory T cells and were also characterized in an aberrantly activated status with an apoptosis-prone potential. In two independent cohorts of HCC patients (n = 358 and n = 254), we demonstrated that PD1 or TIM3PD1 CD8 T cells were significantly correlated with poor prognosis, and the latter was positioned in close proximity to PD-L1 tumor associated macrophages. CONCLUSION: The current study unveils the unique features of PD1 CD8 exhausted T cells in HCC, and also suggests that exhausted T cells could act as a biomarker to select the most care-demanding patients for tailored therapies.
背景：CD8 T 细胞在肿瘤内分化为衰竭状态，包括肝细胞癌（HCC），这构成了有效抗肿瘤免疫的坚实障碍。缺乏对 HCC 中衰竭 T 细胞的详细特征及其预后价值的描述。
方法：我们收集了 56 例 HCC 患者的新鲜肿瘤组织及其相邻非肿瘤肝组织和血液标本，以及两个独立 HCC 患者队列的存档样本（n=358 和 n=254），这些患者接受了手术切除。流式细胞术和多重免疫染色用于鉴定 CD8 T 细胞。通过 Kaplan-Meier 分析和 Cox 回归分析评估患者预后。
结果：CD8 T 细胞分为三个不同的亚群：PD1、PD1 和 PD1。与相邻非肿瘤肝组织相比，PD1 CD8 T 细胞在肿瘤中明显富集。PD1 CD8 T 细胞高度表达衰竭相关抑制受体（TIM3、CTLA-4 等）和转录因子（Eomes、BATF 等）。此外，PD1 CD8 T 细胞表达低水平的细胞毒性分子，在产生促炎细胞因子的能力受损的同时，在有丝分裂刺激下抗炎性 IL-10 的表达上调。此外，PD1 CD8 T 细胞具有组织驻留记忆 T 细胞的特征，并且以异常激活状态和凋亡倾向为特征。在两个独立的 HCC 患者队列（n=358 和 n=254）中，我们证明 PD1 或 TIM3PD1 CD8 T 细胞与预后不良显著相关，后者与 PD-L1 肿瘤相关巨噬细胞密切相关。
结论：本研究揭示了 HCC 中 PD1 CD8 衰竭 T 细胞的独特特征，并提示衰竭 T 细胞可作为生物标志物，选择最需要护理的患者进行针对性治疗。
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