CD155/T cell immunoreceptor with Ig and ITIM domains (TIGIT) is a novel type of immune checkpoint. CD155 is an adhesion molecule that is upregulated during tumor progression and promotes the proliferative and migratory abilities of tumor cells via various pathways. TIGIT, an inhibitory receptor, is mainly expressed on natural killer (NK), CD8 + T, CD4 + T and T regulatory (Treg) cells. CD155 transmits immune signals via interacting with the inhibitory checkpoint receptor TIGIT, thereby inhibiting the function of T and NK cells. Several preclinical studies have supported the use of TIGIT blockade as a monotherapy or combined with other immune checkpoint inhibitors for the treatment of advanced solid malignant tumors. The present review summarized the current knowledge on CD155/TIGIT and the lymphocyte-mediated inhibitory mechanism of CD155/TIGIT. An in-depth understanding of the role of CD155/TIGIT in tumors may aid to improve the application of immune checkpoint inhibitors in tumor therapy.

Transforming growth factor (TGF)-β1 is a key cytokine affecting the pathogenesis and progression of cervical cancer. Tumor-derived exosomes contain microRNAs (miRNAs/miRs) that interact with cancer and stromal cells, thereby contributing to tissue remodeling in the tumor microenvironment (TME). The present study was designed to clarify how TGF-β1 affects tumor biological functions through exosomes released by cervical cancer cells. Deep RNA sequencing found that TGF-β1 stimulated cervical cancer cells to secrete more miR-663b-containing exosomes, which could be transferred into new target cells to promote metastasis. Further studies have shown that miR-663b directly targets the 3′-untranslated regions (3′-UTR) of mannoside acetylglucosaminyltransferase 3 (MGAT3) and is involved in the epithelial-mesenchymal transition (EMT) process. Remarkably, the overexpression of MGAT3 suppressed cervical cancer cell metastasis promoted by exosomal miR-663b, causing increased expression of epithelial differentiation marker E-cadherin and decreased expression of mesenchymal markers N-cadherin and β-catenin. Throughout our study, online bioinformation tools and dual luciferase reporter assay were applied to identify MGAT3 as a novel direct target of miR-663b. Exosome PKH67-labeling experiment verified that exosomal miR-663b could be endocytosed by cervical cancer cells and subsequently influence its migration and invasion functions which were measured by wound healing and Transwell assays. The expression of miR-663b and MGAT3 and the regulation of the EMT pathway caused by MGAT3 were detected by quantitative real-time transcription-polymerase chain reaction (qPCR) and western blot analysis. These results, thus, provide evidence that cancer cell-derived exosomal miR-663b is endocytosed by cervical cancer cells adjacent or distant after TGF-β1 exposure and inhibits the expression of MGAT3, thereby accelerating the EMT process and ultimately promoting local and distant metastasis.

Background Angiogenesis provides essential nutrients and oxygen for tumor growth and has become the main mechanism of tumor invasion and metastasis. Exosomes are nanoscale membrane vesicles containing proteins, lipids, mRNA and microRNA (miRNA), which mediate intercellular communication and play an important role in tumor progression. Accumulated evidence indicates that tumor-derived exosomal miRNAs participate in the tumor microenvironment and promote angiogenesis. Methods Bioinformatic target prediction and dual luciferase reporter assays were performed to identify the binding site between miR-663b and the 3′-UTR of vinculin (VCL). VCL overexpression lentivirus and miR-663b overexpression/inhibition lentivirus were used to create a VCL overexpression model and miR-663b overexpression/inhibition model in-vitro. Immunohistochemistry (IHC) assays and western blot assays were used to detect protein expression. Exosome-cell cocultures, wound healing assays, tube formation assays and transwell assays were used to measure the migration and tube formation ability of vascular endothelial cells [human umbilical vein endothelial cells (HUVECs)]. siRNA targeted VCL was used to knockdown VCL. Results In the present study, we found that miR-663b was elevated in cervical cancer tissue and exosomes. miR-663b could bind the 3′-UTR of VCL and inhibit its expression. VCL is downregulated in cervical cancer, and decreased VCL has a negative correlation with a high level of miR-663b. Further studies demonstrated that exosomes secreted by cervical cancer cells can deliver miR-663b to HUVECs and inhibit the expression of VCL, thereby promoting angiogenesis and tumor growth. Conclusions miR-663b derived from cancer cell exosomes acts as a driving factor for angiogenesis and a potential target of antiangiogenic therapy in cervical cancer. Our findings illustrated a new signaling pathway, including exosomes, miRNAs and target genes, which provides potential targets for antiangiogenic therapy.

Expression of the immunoglobulin superfamily member CD155 was increased in a variety of human malignancies, but the role of CD155 in tumorigenesis and tumor development in cervical cancer has not been elucidated. In this study, immunohistochemistry and enzyme-linked immunosorbent assay analyses showed that CD155 expression gradually increases with the degree of cervical lesions. In vitro and in vivo, reducing the expression of CD155 inhibited cell proliferation, cell viability and tumor formation and arrested the cell cycle in G0/G1 phase. Antibody array-based profiling of protein phosphorylation revealed that CD155 knockdown can inhibited the AKT/mTOR/NF-κB pathway and activated autophagy and apoptosis; the opposite effects were observed upon CD155 has overexpression. We proved that there is an interaction between CD155 and AKT by immunoprecipitation. We further confirmed the mechanism between CD155 and AKT/mTOR/NF-κB through rescue experiments. AKT knockdown reversed the anti-apoptotic effects and activation of the AKT/mTOR/NF-κB pathway induced by CD155 overexpression. Our research demonstrated that CD155 can interact with AKT to form a complex, activates the AKT/mTOR/NF-κB pathway and inhibit autophagy and apoptosis. Thus, CD155 is a potential screening and therapeutic biomarker for cervical cancer.