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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 …