*Department of Endoscopy †State Key Laboratory of Oncology in South China §Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center ‡Haizhu District Center for Disease Control and Prevention, Guangzhou, P.R. China.
J Immunother. 2017 Nov/Dec;40(9):323-333. doi: 10.1097/CJI.0000000000000187.
As PD-1/PD-L1 immune checkpoint inhibitors exhibited promising clinical outcomes in various types of solid tumors, PD-1/PD-L1 blockades have been explored for the treatment of hepatocellular carcinoma (HCC). However, the association of PD-L1 with antitumor immunoregulation is not clearly defined in HCC. Here, we evaluated the characteristics of PD-L1 expression, CD8 T-cell infiltration and their relationship in HCC. A total of 411 resected tumor specimens from HCC patients were immunostained for PD-L1 and CD8. Only 78 (19%) cases showed ≥5% membranous PD-L1 expression on tumor cells, although a significantly positive correlation was found between PD-L1 expression and CD8 T-cell densities. Moreover, patients with higher tumor PD-L1 expression also showed a higher hepatitis B virus load, which was also related to increased CD8 infiltration. Survival analysis suggested that both tumor and stroma PD-L1 status did not significantly affect overall survival or recurrence-free survival in patients. Although high CD8 T-cell density was overall associated with better overall survival and recurrence-free survival, its favorable prognostic value was eliminated by high tumor PD-L1 expression. Further flow cytometric and enzyme-linked immunosorbent assay (ELISA) results from the coculture of HCC cell lines with specific CD8 cytotoxic T lymphocytes (CTLs) demonstrated that CD8 CTLs remarkably upregulated PD-L1 expression on tumor cell lines by HLA class-I specificity, and the overexpression of tumor PD-L1 impaired interferon-γ secretion by CD8 CTLs in a negative feedback regulation mechanism. In conclusion, our findings reveal an interaction between PD-L1 expression and CD8 T-cell immunity in HCC, although PD-L1 is not a prognostic factor for the patients.
由于 PD-1/PD-L1 免疫检查点抑制剂在各种实体肿瘤中显示出有前景的临床结果，因此已经探索了 PD-1/PD-L1 阻断剂用于治疗肝细胞癌（HCC）。然而，PD-L1 与 HCC 中的抗肿瘤免疫调节之间的关联尚不清楚。在这里，我们评估了 PD-L1 表达、CD8 T 细胞浸润及其在 HCC 中的关系的特征。对 411 例 HCC 患者的肿瘤标本进行了 PD-L1 和 CD8 的免疫染色。尽管在 PD-L1 表达与 CD8 T 细胞密度之间发现了显著的正相关，但只有 78 例（19％）病例的肿瘤细胞上显示出≥5％的膜 PD-L1 表达。此外，具有较高肿瘤 PD-L1 表达的患者还显示出较高的乙型肝炎病毒载量，这也与 CD8 浸润增加有关。生存分析表明，肿瘤和基质 PD-L1 状态均未显著影响患者的总生存或无复发生存率。尽管高 CD8 T 细胞密度总体上与更好的总生存和无复发生存率相关，但高肿瘤 PD-L1 表达消除了其有利的预后价值。从 HCC 细胞系与特异性 CD8 细胞毒性 T 淋巴细胞（CTL）的共培养中进行的进一步流式细胞术和酶联免疫吸附测定（ELISA）结果表明，CD8 CTL 通过 HLA Ⅰ类特异性显著上调肿瘤细胞系上的 PD-L1 表达，并且肿瘤 PD-L1 的过表达以负反馈调节机制损害 CD8 CTL 中干扰素-γ的分泌。总之，我们的研究结果揭示了 HCC 中 PD-L1 表达与 CD8 T 细胞免疫之间的相互作用，尽管 PD-L1 不是患者的预后因素。
