Immune checkpoints include stimulatory and inhibitory checkpoint molecules. In recent years, inhibitory checkpoints, including cytotoxic T lymphocyte–associated antigen 4 (CTLA-4), programmed cell death protein-1 (PD-1), and programmed cell death ligand 1 (PD-L1), have been identified to suppress anti-tumor immune responses in solid tumors. Novel drugs targeting immune checkpoints have succeeded in cancer treatment. Specific PD-1 blockades were approved for treatment of melanoma in 2014 and for treatment of non-small-cell lung cancer in 2015 in the United States, European Union, and Japan. Preclinical and clinical studies show immune checkpoint therapy provides survival benefit for greater numbers of patients with liver cancer, including hepatocellular carcinoma and cholangiocarcinoma, two main primary liver cancers. The combination of anti-PD-1/PD-L1 with anti-CTLA-4 antibodies is being evaluated in phase 1, 2 or 3 trials, and the results suggest that an anti-PD-1 antibody combined with locoregional therapy or other molecular targeted agents is an effective treatment strategy for HCC. In addition, studies on activating co-stimulatory receptors to enhance anti-tumor immune responses have increased our understanding regarding this immunotherapy in liver cancer. Epigenetic modulations of checkpoints for improving the tumor microenvironment also expand our knowledge of potential therapeutic targets in improving the tumor microenvironment and restoring immune recognition and immunogenicity. In this review, we summarize current knowledge and recent developments in immune checkpoint-based therapies for the treatment of hepatocellular carcinoma and cholangiocarcinoma and attempt to clarify the mechanisms underlying its effects.

T cell immunoglobulin and ITIM domain (TIGIT) and CD226 emerge as a novel T cell cosignaling pathway in which CD226 and TIGIT serve as costimulatory and coinhibitory receptors, respectively, for the ligands CD155 and CD112. In this study, we describe CD112R, a member of poliovirus receptor–like proteins, as a new coinhibitory receptor for human T cells. CD112R is preferentially expressed on T cells and inhibits T cell receptor–mediated signals. We further identify that CD112, widely expressed on antigen-presenting cells and tumor cells, is the ligand for CD112R with high affinity. CD112R competes with CD226 to bind to CD112. Disrupting the CD112R–CD112 interaction enhances human T cell response. Our experiments identify CD112R as a novel checkpoint for human T cells via interaction with CD112.

Cancer immunotherapy has been a great breakthrough, with immune checkpoint inhibitors leading the way. Despite the clinical effectiveness of certain immune checkpoint inhibitors, the overall response rate remains low, and the effectiveness of immunotherapies for many tumors has been disappointing. There is substantial interest in looking for additional immune checkpoint molecules that may act as therapeutic targets for cancer. Recent advances during the last decade have identified several novel immune checkpoint targets, including lymphocyte activation gene-3 (LAG-3), B and T lymphocyte attenuator (BTLA), programmed death-1 homolog (PD-1H), T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIM-3)/carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1), and the poliovirus receptor (PVR)-like receptors. The investigations into these molecules have generated promising results in preclinical studies. Herein, we will summarize our current progress and understanding of these newly-characterized immune checkpoints and their potential application in cancer immunotherapy.

The CD28H/B7-H5 pathway is a newly identified pathway of the B7 family. In human peripheral blood, the receptor CD28H is preferentially expressed on naïve T cells and repetitive stimulation of T cells leads to the loss of CD28H expression. Here we examined the expression of the CD28H/B7-H5 pathway in human peripheral tissues, as well as in human cancers. We found that CD28H is preferentially expressed on T cells with tissue-resident phenotypes (T_RM). Supporting that, stimulation via IL-15 and TGF-β, presumably major cytokines essential for T_RM cell homeostasis, sustains CD28H expression on T cells. The ligand B7-H5 is constitutively expressed on normal epithelium of human oral-gastrointestinal tracts. In human cancers, CD28H is preferentially present on tumor infiltrating lymphocytes (TILs) with T_RM features and identifies a T_RM subset with less cytotoxicity. Taken together, our studies suggest that the CD28H/B7-H5 pathway involves the interactions between T_RM cells and epithelium, and could be important for human T_RM homeostasis and function.