The recent discovery of immune checkpoint inhibitors is a significant milestone in cancer immunotherapy research. However, some patients with primary or adaptive drug resistance might not benefit from the overall therapeutic potential of immunotherapy in oncology. Thus, it is becoming increasingly critical for oncologists to explore the availability of new immune checkpoint inhibitors. An emerging co-inhibitory receptor, CD112R (also called PVRIG), is most commonly expressed on natural killer (NK) and T cells. It binds to its ligand (CD112 or PVRL2/nectin-2) and inhibits the strength with which T cells and NK cells respond to cancer. Therefore, CD112R is being presented as a new immune checkpoint inhibitor with high potential in cancer immunotherapy. CD112 is easily detectable on antigen-presenting or tumor cells, and its high level of expression has been linked with tumor progression and poor outcomes in most cancer patients. This review explores the molecular and functional relationship between CD112R, TIGIT, CD96, and CD226 in T cell responses. In addition, this review comprehensively discusses the recent developments of CD112R/CD112 immune checkpoints in cancer immunotherapy and prognosis.

Hepatocellular carcinoma (HCC) constitutes most primary liver cancers and is one of the most lethal and life-threatening malignancies globally. Unfortunately, a substantial proportion of HCC patients are identified at an advanced stage that is unavailable for curative surgery. Thus, palliative therapies represented by multi-tyrosine kinase inhibitors (TKIs) sorafenib remained the front-line treatment over the past decades. Recently, the application of immune checkpoint inhibitors (ICIs), especially targeting the PD-1/PD-L1/CTLA-4 axis, has achieved an inspiring clinical breakthrough for treating unresectable solid tumors. However, many HCC patients with poor responses lead to limited benefits in clinical applications, which has quickly drawn researchers’ attention to the regulatory mechanisms of immune checkpoints in HCC immune evasion. Evasion of immune surveillance by cancer is attributed to intricate reprogramming modulation in the tumor microenvironment. Currently, more and more studies have found that epigenetic modifications, such as chromatin structure remodeling, DNA methylation, histone post-translational modifications, and non-coding RNA levels, may contribute significantly to remodeling the tumor microenvironment to avoid immune clearance, affecting the efficacy of immunotherapy for HCC. This review summarizes the rapidly emerging progress of epigenetic-related changes during HCC resistance to ICIs and discusses the mechanisms of underlying epigenetic therapies available for surmounting immune resistance. Finally, we summarize the clinical advances in combining epigenetic therapies with immunotherapy, aiming to promote the formation of immune combination therapy strategies.

Background: Non-alcoholic fatty liver disease (NAFLD) has gradually emerged as the most prevalent cause of chronic liver diseases. However, specific changes during the progression of NAFLD from non-fibrosis to advanced fibrosis and then hepatocellular carcinoma (HCC) are unresolved. Here, we firstly identify the key gene linking NAFLD fibrosis and HCC through analysis and experimental verification.Methods: Two GEO datasets (GSE89632, GSE49541) were performed for identifying differentially expressed genes (DEGs) associated with NAFLD progression from non-fibrosis to early fibrosis and eventually to advanced fibrosis. Subsequently, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analysis, protein-protein interaction (PPI) network were integrated to explore the potential function of the DEGs and hub genes. The expression of NUSAP1 was confirmed in vivo and in vitro NAFLD models at mRNA and protein level. Then, cell proliferation and migration under high fat conditions were verified by cell counting kit-8 (CCK-8) and wound-healing assays. The lipid content was measured with Oil Red O staining. Finally, the analysis of clinical survival curves was performed to reveal the prognostic value of the crucial genes among HCC patients via the online web-tool GEPIA2 and KM plotter.Results: 5510 DEGs associated with non-fibrosis NAFLD, 3913 DEGs about NAFLD fibrosis, and 739 DEGs related to NAFLD progression from mild fibrosis to advanced fibrosis were identified. Then, a total of 112 common DEGs were found. The result of enrichment analyses suggested that common DEGs were strongly associated with the glucocorticoid receptor pathway, regulation of transmembrane transporter activity, peroxisome, and proteoglycan biosynthetic process. Six genes, including KIAA0101, NUSAP1, UHRF1, RAD51AP1, KIF22, and ZWINT, were identified as crucial candidate genes via the PPI network. The expression of NUSAP1 was validated highly expressed in vitro and vivo NAFLD models at mRNA and protein level. NUSAP1 silence could inhibit the ability of cell proliferation, migration and lipid accumulation in vitro. Finally, we also found that NUSAP1 was significantly up-regulated at transcriptional and protein levels, and associated with poor survival and advanced tumor stage among HCC patients.Conclusion: NUSAP1 may be a potential therapeutic target for preventing NAFLD progression to liver cancer.

Polymorphisms in interleukin-4 receptor (IL-4R) gene have been reported susceptible to a variety of cancer types, nevertheless, data from these publications remained inconsistent and controversial. We further performed a comprehensive meta-analysis to present a precise estimation of its relationship. Extensive retrieve was performed in PubMed, Google Scholar and Web of Science up to May 25, 2018. Odds ratios (ORs) and 95% confidence intervals (CIs) were conducted to evaluate the overall strength of the associations in five genetic models, as well as in subgroup analyses, stratified by ethnicity, cancer type or source of control. Q-test, Egger's test and Begg's funnel plot were applied to evaluate the heterogeneity and publication bias. In-silico analysis was managed to demonstrate the relationship of IL-4R expression correlated with cancer tissues. Finally, 31 publications including 53 case-control studies were enrolled, with 24,452 cases and 24,971 controls. After a comprehensive analysis, no significant evidence was revealed for the association between four IL-4R polymorphisms (rs1801275, rs1805010, rs1805015, rs2057768) and cancer susceptibility in the overall population, as well as the subgroup analysis stratified by ethnicity, cancer type, the genotyping method or the source of control. To sum up, no evidence was identified between IL-4R polymorphisms and overall cancer susceptibility. Further well-designed studies with large sample sizes will be continued on this issue of interest.

BackgroundEnergy metabolism has been considered as one of the novel features of neoplasms. This study aimed to establish the prognostic signature for pancreatic cancer (PC) based on metabolism-related genes (MRGs).MethodsWe obtained MRGs from the Molecular Signatures Database (MSigDB) and gene sequence data in the Cancer Genome Atlas (TCGA) databases. Then, differentially expressed MRGs (DE-MRGs) were identified utilizing the R software. We built the prognostic model via multivariate Cox regression. Moreover, external validation of the prognostic signature was also performed. Nomogram was created to predict the overall survival (OS). Next, this study analyzed the prognostic value, clinical relationship, and metabolism-related signaling pathways of the prognostic signature. The role in tumor infiltration was further evaluated. Eventually, the expression level of the three MRGs along with the function of NT5E was validated.ResultsTwenty-two MRGs were chosen, eight of which were identified to be most significantly correlated with the prognosis of PC. Meanwhile, a 3-MRG prognostic signature was established, and we verified this prognostic model in two separate external cohorts. What is more, the nomogram was used to predict 1-/2-/3-year OS of PC patients. In addition, the immune cell infiltration and expression of immune checkpoint were significantly influenced by the risk score. Finally, three MRGs were highly expressed in PC cell lines, and NT5E was associated with the proliferation and migration ability of PC.ConclusionTo sum up, the study established and validated a 3-MRG prognostic signature for PC, and the signature could be utilized to predict the prognosis and assist the individualized clinical management of patients with PC.