Human CD96 Correlates to Natural Killer Cell Exhaustion and Predicts the Prognosis of Human Hepatocellular Carcinoma

作者：Haoyu Sun, Qiang Huang, Mei Huang, Hao Wen, Renyong Lin, Meijuan Zheng, Kun Qu, Kun Li, Haiming Wei, Weihua Xiao, Rui Sun, Zhigang Tian, Cheng Sun · 发表于：Hepatology · 年份：2018 · DOI：10.1002/hep.30347 · 被引用次数：325 · 研究领域：Immune Cell Function and Interaction、Immune cells in cancer、Cancer Immunotherapy and Biomarkers

Immune checkpoint blockade has become a promising therapeutic approach to reverse immune cell exhaustion. Coinhibitory CD96 and T‐cell immunoglobulin and ITIM domain (TIGIT), together with costimulatory CD226, bind to common ligand CD155. The balancing between three receptors fine‐tunes immune responses against tumors. In this study, we investigated the expression of CD96, TIGIT, and CD226 in 55 fresh human hepatocellular carcinoma (HCC) samples, 236 paraffin‐embedded HCC samples, and 20 normal human livers. The cumulative percentage, absolute count, and mean fluorescence intensity (MFI) of CD96 + NK cells are significantly increased in the intratumoral tissues of HCC and break the balance between three receptors. Human CD96 + NK cells are functionally exhausted with impaired interferon‐gamma (IFN‐γ) and tumor necrosis factor‐alpha (TNF‐α) production, high gene expression of interleukin (IL)‐10 and transforming growth factor‐beta 1 (TGF‐β1), and low gene expression of T‐bet, IL‐15, perforin, and granzyme B. In addition, blocking CD96‐CD155 interaction specifically increases lysis of HepG2 cells by NK cells. HCC patients with a high level of CD96 or CD155 expression within tumor are strongly associated with deteriorating disease condition and shorter disease‐free survival (DFS) and overall survival times. Patients with a higher cumulative percentage of CD96 + NK cells within tumor also exhibit shorter DFS. High plasma level of TGF‐β1 in HCC patients up‐regulates CD96 expressio...