PD1Hi CD8+ T cells correlate with exhausted signature and poor clinical outcome in hepatocellular carcinoma
PD1Hi CD8+ T cells correlate with exhausted signature and poor clinical outcome in hepatocellular carcinoma
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PD1HiCD8 T 细胞与肝细胞癌的衰竭特征和不良临床结果相关
DOI：
10.1186/s40425-019-0814-7
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发表时间：
2019-11-29
影响因子：
10.9
通讯作者：
Zhang, Xiaoming
中科院分区：
文献类型：
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作者：
Jiaqiang;Zheng, Bohao;Zhang, Xiaoming
背景CD 8（+）T细胞在包括肝细胞癌（HCC）在内的肿瘤中分化为耗竭状态，这构成了有效抗肿瘤免疫的坚实屏障。缺乏耗尽的T细胞的详细特征及其在HCC中的预后价值。方法收集56例HCC患者的新鲜肿瘤组织、邻近非肿瘤肝组织和血液标本，以及两个独立队列（n = 358和n = 254）接受手术切除的HCC患者的存档标本。流式细胞术和多重免疫染色用于表征CD 8（+）T细胞。Kaplan-Meier分析和考克斯回归分析评估患者预后。结果CD 8（+）T细胞可分为3个亚群：PD 1（Hi）、PD 1（Int）和PD 1（-）。与邻近的非肿瘤肝组织相比，PD 1（Hi）CD 8（+）T细胞在肿瘤中显著富集。PD 1（Hi）CD 8（+）T细胞高表达衰竭相关抑制性受体（TIM 3、CTLA-4等）和转录因子（Eomes、BATF等）。此外，PD 1（Hi）CD 8（+）T细胞表达低水平的细胞毒性分子，并显示出产生促炎细胞因子的能力受损，而抗炎IL-10的表达在有丝分裂刺激后上调。此外，PD 1（Hi）CD 8（+）T细胞与组织驻留记忆T细胞具有共同的特征，并且还以具有潜在的免疫缺陷倾向的异常激活状态为特征。在两个独立的HCC患者队列（n = 358和n = 254）中，我们证明PD 1（Hi）或TIM 3（+）PD 1（Hi）CD 8（+）T细胞与不良预后显著相关，后者位于PD-L1（+）肿瘤相关巨噬细胞附近。结论本研究揭示了HCC中PD 1（Hi）CD 8（+）耗竭T细胞的独特特征，并提示耗竭T细胞可作为生物标志物，选择最需要护理的患者进行定制治疗。
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(Hi), PD1(Int) and PD1(-). PD1(Hi) CD8(+) T cells were significantly enriched in tumor compared to adjacent non-tumor liver tissues. PD1(Hi) CD8(+) T cells highly expressed exhaustion-related inhibitory receptors (TIM3, CTLA-4, etc.) and transcription factors (Eomes, BATF, etc.). In addition, PD1(Hi) 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(Hi) 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(Hi) or TIM3(+)PD1(Hi) 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(Hi) 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.