Immune checkpoint molecules, also known as cosignaling molecules, are pivotal cell-surface molecules that control immune cell responses by either promoting (costimulatory molecules) or inhibiting (coinhibitory molecules) a signal. These molecules have been studied for many years. The application of immune checkpoint drugs in the clinic provides hope for cancer patients. Recently, the poliovirus receptor (PVR)-like protein cosignaling network, which involves several immune checkpoint receptors, i.e., DNAM-1 (DNAX accessory molecule-1, CD226), TIGIT (T-cell immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibitory motif (ITIM)), CD96 (T cell activation, increased late expression (TACLILE)), and CD112R (PVRIG), which interact with their ligands CD155 (PVR/Necl-5), CD112 (PVRL2/nectin-2), CD111 (PVRL1/nectin-1), CD113 (PVRL3/nectin-3), and Nectin4, was discovered. As important components of the immune system, natural killer (NK) and T cells play a vital role in eliminating and killing foreign pathogens and abnormal cells in the body. Recently, increasing evidence has suggested that this novel cosignaling network axis costimulates and coinhibits NK and T cell activation to eliminate cancer cells after engaging with ligands, and this activity may be effectively targeted for cancer immunotherapy. In this article, we review recent advances in research on this novel cosignaling network. We also briefly outline the structure of this cosignaling network, the signaling cascades and mechanisms involved after receptors engage with ligands, and how this novel cosignaling network costimulates and coinhibits NK cell and T cell activation for cancer immunotherapy. Additionally, this review comprehensively summarizes the application of this new network in preclinical trials and clinical trials. This review provides a new immunotherapeutic strategy for cancer treatment.

No abstract

Long noncoding RNA H19 (H19) is an imprinting gene with only maternal expression that is involved in regulating different processes in various types of cells. Previous studies have shown that abnormal H19 expression is involved in many pathological processes, such as cancer, mainly through sponging miRNAs, interacting with proteins, or regulating epigenetic modifications. Accumulating evidence has shown that several oncogenic signaling pathways lead to carcinogenesis. Recently, the regulatory relationship between H19 and oncogenic signaling pathways in various types of cancer has been of great interest to many researchers. In this review, we discussed the key roles of H19 in cancer development and progression via its regulatory function in several oncogenic signaling pathways, such as PI3K/Akt, canonical Wnt/β-catenin, canonical NF-κB, MAPK, JAK/STAT and apoptosis. These oncogenic signaling pathways regulated by H19 are involved in cell proliferation, proliferation, migration and invasion, angiogenesis, and apoptosis of various cancer cells. This review suggests that H19 may be a novel therapeutic target for cancers treatment by regulating oncogenic signaling pathways.

Advanced gallbladder cancer (GBC) is one of the most malignant of all types of biliary tract cancers that is associated with poor prognosis and high mortality. Accumulating evidence suggest that the B7 family of proteins serve an essential role in various types of cancers, including GBC. However, the potential function and regulatory mechanism of human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2; also known as B7-H7 or B7H5) in GBC remain poorly understood. In the present study, immunohistochemistry was used to examine the expression pattern of HHLA2 in samples from 89 patients with GBC. The possible association between HHLA2 expression and the clinicopathological parameters, including prognosis, were then assessed. Using lentiviruses, overexpression of HHLA2 plasmid or short-hairpin RNA (shRNA) of HHLA2 were transfected into GBC-SD cells to overexpress or knock down HHLA2 expression, respectively. The effects of HHLA2 overexpression and knockdown on the epithelial-mesenchymal transition (EMT) process on GBC-SD cells were measured by the western blotting and immunofluorescence staining of collagen I, N-cadherin, E-cadherin, vimentin and α-SMA. By contrast, changes in cell proliferation were measured using EdU assay. Cell invasion and migration were assessed using Transwell and wound-healing assays, respectively. In addition, a xenograft mouse model was established to evaluate the tumorigenic ability of the GBC cell line in vivo after stable transfection with lentivirus for HHLA2 overexpression or shRNA for HHLA2 knockdown. The regulatory relationships among TGF-β1, long non-coding RNA (lncRNA) H19 (H19) and HHLA2 were then investigated. The mRNA expression of lncRNA H19 were assessed using reverse transcription-quantitative PCR, whereas the expression levels of HHLA2 were detected by western blotting and immunofluorescence staining. HHLA2 expression was found to gradually increase as the stages of the GBC samples become more advanced. In addition, the expression level of HHLA2 was calculated to be positively associated with the Nevin stage, American Joint Committee on Cancer stage, tumor invasion and regional lymph node metastasis but was negatively associated with the overall patient survival (OS). In vitro experiments demonstrated that overexpression of HHLA2 promoted GBC migration, invasion, proliferation and EMT, whereas in vivo experiments found a promoting role of HHLA2 overexpression on GBC tumor growth. After transfection with lentiviruses encoding the overexpression plasmid of lncRNA H19, GBC migration, invasion, proliferation and EMT were increased. By contrast, knocking down HHLA2 expression suppressed TGF-β1- or lncRNA H19 overexpression-induced GBC migration, invasion, proliferation and EMT. In addition, HHLA2 knockdown significantly reduced the sizes of the GBC tumors in vivo . These results suggest that HHLA2 overexpression can promote GBC progression. Conversely, ablation...

BackgroundImmunotherapy has achieved great success in cancer. Nevertheless, many patients cannot benefit from immune checkpoint blockade therapy because of the scantiness of CD8+ T cell infiltration in the tumor microenvironment (TME). CXCL11 is known as a regulator that influences T-cell infiltration into tumors. However, the role of CXCL11 in pan-cancer is still unclear.MethodsIn this study, we investigated the expression and function of CXCL11 across 33 types of cancers based on datasets from The Cancer Genome Atlas (TCGA) database and the Genotype-Tissue Expression (GTEx) database. We analyzed the CXCL11 differential expression in tumor tissue and nontumoral tissue and in different stages of cancers. Moreover, the correlations among CXCL11 expression, prognosis, mismatch repair, tumor mutation burden (TMB), microsatellite instability (MSI), tumor microenvironment, and immune-related genes were evaluated.ResultsCXCL11 expression was significantly higher in tumoral tissue than in nontumoral tissue for most types of cancer. Improved CXCL11 expression was related to an inconsistent prognosis in different cancers. CXCL11 was positively associated with CD8+ T cells and T follicular helper cells in the TME. High expression of CXCL11 was positively related to TMB in BLCA, BRCA, CESC, COAD, LGG, LUAD, OV, SKCM, STAD, THYM, and UCEC. A positive correlation between CXCL11 and MSI was found in COAD and UVM. Moreover, functional analysis of CXCL11 showed that high CXCL11 expression was significantly related to immune-relevant pathways.ConclusionsCXCL11 might function as a prognostic and immunotherapy marker across cancers. Further investigation into CXCL11 might provide promising insights to improve cancer therapy.