HCC microenvironment breaks the balance between CD96, TIGIT, and CD226 on NK cells by increasing expression of CD96, which, in turn, impairs the antitumor immune responses of NK cells. Postulated mechanisms showing inhibitory receptor CD96, as well as its ligand CD155, significantly expand in the cancer nest. Induction of CD96 on NK cells and the binding with their ligand CD155 on tumor cells specifically impairs cytotoxicity and cytokine secretion of NK cells, contributing to immune escape in HCC. (Hepatology, Vol. 70, No. 1, 2019)

As the predominant lymphocyte subset in the liver, natural killer (NK) cells have been shown play an important role for tumor controlling of liver and be highly correlated with hepatocellular carcinoma (HCC) patient outcomes. Previously, we reported that NK cells were functionally deficient and that their levels were significantly decreased in HCC, but the mechanism underlying hepatic NK cell deficient is poorly understood. Here, we demonstrated that multiple checkpoints not only contribute to NK cell exhaustion but also an important predictor in HCC patients.These data opens new possibilities to dissect this complex NK cell exhaustion mechanism in tumor patients, and demonstrate the therapeutic potential of these checkpoint candidates for cancer immunotherapy. (Cancer Res. 2018 Sep 19.CAN-18-1049/Oncoimmunology. Volume 6, 2017 6(1):e1264562./ Front Immunol. 2019 Oct 17;10:2354)