Blocking Tim-3 or/and PD-1 reverses dysfunction of tumor-infiltrating lymphocytes in HBV-related hepatocellular carcinoma
Blocking Tim-3 or/and PD-1 reverses dysfunction of tumor-infiltrating lymphocytes in HBV-related hepatocellular carcinoma
复制标题
阻断 Tim-3 或/和 PD-1 可逆转 HBV 相关肝细胞癌中肿瘤浸润淋巴细胞的功能障碍
DOI：
10.1016/j.bulcan.2018.01.018
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发表时间：
2018-05-01
影响因子：
1.2
通讯作者：
Hu, Anbin
中科院分区：
文献类型：
--
作者：
Liu, Furong;Zeng, Gucheng;Hu, Anbin
肿瘤浸润淋巴细胞（TILs）的免疫抑制与乙型肝炎病毒相关性肝细胞癌（HBV-HCC）的快速进展有关。T细胞Ig-和粘蛋白结构域分子-3 （Tim-3）和程序性细胞死亡1 （PD-1）是T细胞表面表达的重要抑制分子，但它们在HBV-HCC中TILs功能中的作用尚不清楚。我们的目的是研究这两种标志物在HBV-HCC中的作用。方法90例经病理证实的HBV相关HCC患者加入我们的研究。采集血样、配对的新鲜肿瘤组织及邻近组织，分离外周血单个核细胞、TILs及邻近浸润淋巴细胞。对患者进行随访以进行生存分析。结果HBV-HCC患者CD4（+）和CD8(+) TILs上> Tim-3或/和PD-1表达上调，且单独表达PD-1的TILs比例更高。Tim-3（+）和PD-1(+) TILs显著降低ifn - γ和tnf - α的分泌。TILs上Tim-3和PD-1的表达与HCC患者无病生存率呈负相关。体外直接阻断Tim-3和PD-1可显著增强TILs的增殖和ifn - γ和tnf - α的分泌。结论Tim-3和/或PD-1在肝细胞癌til上的表达可损害til的功能，并与无病生存期呈负相关。直接阻断Tim-3和PD-1可恢复TILs的抗肿瘤作用，这提示了HBV-HCC新型免疫治疗的潜在靶点。
Background > The immunosuppression of tumor-infiltrating lymphocytes (TILs) is associated with rapid progression of hepatitis B virus-related hepatocellular carcinoma (HBV-HCC). T cell Ig- and mucin-domain-containing molecule-3 (Tim-3) and programmed cell death 1 (PD-1) are important inhibitory molecules expressed on the surface of T cells, but their roles in the function of TILs in HBV-HCC are poorly understood. We aimed to study the roles of these two markers in HBV-HCC.Methods > Ninety patients with pathologically confirmed HBV- associated HCC were enrolled in our study. Blood samples, paired fresh tumor tissues and adjacent tissues were collected, and isolating peripheral blood mononuclear cells, TILs and adjacent-infiltrating lymphocytes were isolated from these samples. The patients were followed-up to allow survival analysis.Results > Tim-3 or/and PD-1 was up-regulated expressed on CD4(+) and CD8(+) TILs in HBV-HCC patients and a higher proportion of TILs expressed PD- 1 alone. Tim-3(+) and PD-1(+) TILs greatly decreased secretion of IFN-gamma and TNF-alpha. Expression of Tim-3 and PD-1 on TILs negatively correlated with disease-free survival of HCC patients. Direct blockade of Tim-3 and PD-1 in vitro significantly enhanced TILs proliferation and secretion of IFN-gamma and TNF-alpha.Conclusion > Expression of Tim-3 and/or PD-1 on TILs impairs their function and correlates negatively with disease-free survival in HBV-HCC. Direct blockade of Tim-3 and PD-1 restores anti-tumor effects of TILs, which suggests a potential target for novel immunotherapy in HBV-HCC.