T cell-derived interleukin-22 drives the expression of CD155 by cancer cells to suppress NK cell function and promote metastasis.

Although T cells can exert potent anti-tumor immunity, a subset of T helper (Th) cells producing interleukin-22 (IL-22) in breast and lung tumors is linked to dismal patient outcome. Here, we examined the mechanisms whereby these T cells contribute to disease. In murine models of lung and breast cancer, constitutional and T cell-specific deletion of Il22 reduced metastases without affecting primary tumor growth. Deletion of the IL-22 receptor on cancer cells decreases metastasis to a degree similar to that seen in IL-22-deficient mice. IL-22 induced high expression of CD155, which bound to the activating receptor CD226 on NK cells. Excessive activation led to decreased amounts of CD226 and functionally impaired NK cells, which elevated the metastatic burden. IL-22 signaling was also associated with CD155 expression in human datasets and with poor patient outcomes. Taken together, our findings reveal an immunosuppressive circuit activated by T cell-derived IL-22 that promotes lung metastasis.

CD155 on Tumor Cells Drives Resistance to Immunotherapy by Inducing the Degradation of the Activating Receptor CD226 in CD8+ T Cells.

The activating receptor CD226 is expressed on lymphocytes, monocytes, and platelets and promotes anti-tumor immunity in pre-clinical models. Here, we examined the role of CD226 in the function of tumor-infiltrating lymphocytes (TILs) and resistance to immunotherapy. In murine tumors, a large proportion of CD8+ TILs had decreased surface expression of CD226 and exhibited features of dysfunction, whereas CD226hi TILs were highly functional. This correlation was seen also in TILs isolated from HNSCC patients. Mutation of CD226 at tyrosine 319 (Y319) led to increased CD226 surface expression, enhanced anti-tumor immunity and improved efficacy of immune checkpoint blockade (ICB). Mechanistically, tumor-derived CD155, the ligand for CD226, initiated phosphorylation of Y319 by Src kinases, thereby enabling ubiquitination of CD226 by CBL-B, internalization, and proteasomal degradation. In pre-treatment samples from melanoma patients, CD226+CD8+ T cells correlated with improved progression-free survival following ICB. Our findings argue for the development of therapies aimed at maintaining the expression of CD226.

Tumor FAK orchestrates immunosuppression in ovarian cancer via the CD155/TIGIT axis.

High-grade serous ovarian cancer (HGSOC) is a lethal malignancy characterized by an immunosuppressive tumor microenvironment containing few tumor infiltrating lymphocytes (TILs) and an insensitivity to checkpoint inhibitor immunotherapies. Gains in the PTK2 gene encoding focal adhesion kinase (FAK) at Chr8 q24.3 occur in ∼70% of HGSOC tumors, and elevated FAK messenger RNA (mRNA) levels are associated with poor patient survival. Herein, we show that active FAK, phosphorylated at tyrosine-576 within catalytic domain, is significantly increased in late-stage HGSOC tumors. Active FAK costained with CD155, a checkpoint receptor ligand for TIGIT (T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains), in HGSOC tumors and a selective association between FAK and TIGIT checkpoint ligands were supported by patient transcriptomic database analysis. HGSOC tumors with high FAK expression were associated with low CD3 mRNA levels. Accordingly, late-stage tumors showed elevated active FAK staining and significantly lower levels of CD3+ TILs. Using the KMF (Kras, Myc, FAK) syngeneic ovarian tumor model containing spontaneous PTK2 (FAK) gene gains, the effects of tumor intrinsic genetic or oral small molecule FAK inhibitior (FAKi; VS-4718) were evaluated in vivo. Blocking FAK activity decreased tumor burden, suppressed ascites KMF-associated CD155 levels, and increased peritoneal TILs. The combination of FAKi with blocking TIGIT antibody (1B4) maintained elevated TIL levels and reduced TIGIT+ T regulatory cell levels, prolonged host survival, increased CXCL13 levels, and led to the formation of omental tertiary lymphoid structures. Collectively, our studies support FAK and TIGIT targeting as a rationale immunotherapy combination for HGSOC.

Expression of the immune checkpoint molecules CD226 and TIGIT in preeclampsia patients.

BACKGROUND: Imbalanced immune responses are involved in developing preeclampsia (PE). We wish to explore the expression and potential changes of immune checkpoint molecules TIGIT, CD226 and CD155 in PE patients. METHODS: The expression of the immune checkpoint molecules TIGIT, CD226 and CD155 in different lymphocyte subpopulations was determined by flow cytometry in 24 patients with PE and compared to 24 healthy pregnant women of the same gestational age as the controls.​Serum CD155 was detected by ELISA in the patients with PE compared to controls. RESULTS: The percentages of CD4+ and CD8+ T lymphocytes in the peripheral blood of PE patients were not significantly different from those of the controls, whereas the regulatory T cells (Tregs) in PE patients were significantly lower than those in controls (6.43 ± 1.77% vs. 7.48 ± 1.71%, P = 0.0420). The expression of TIGIT and CD226 showed different percentages on CD4+ T cells, CD8+ T cells and Treg cells. However, the difference in the percentages of TIGIT, CD226 on these T cells between the two groups was not statistically significant. The level of CD155 in peripheral serum of PE patients was 6.64 ± 1.79 ng/ml, which was not significantly different from that in the control group 5.61 ± 1.77 ng/ml, P = 0.0505. The present results demonstrate that TIGIT, CD226 and CD155 are not present at altered immune conditions in the peripheral blood of patients with PE, compared with normal pregnant women. CONCLUSION: The immune checkpoint molecules TIGIT, CD226 and CD155 are not abnormally expressed in PE patients.

The immune checkpoint TIGIT/CD155 promotes the exhaustion of CD8 + T cells in TNBC through glucose metabolic reprogramming mediated by PI3K/AKT/mTOR signaling.

OBJECTIVE: The CD155/TIGIT axis has attracted considerable interest as an emerging immune checkpoint with potential applications in cancer immunotherapy. Our research focused on investigating the role of CD155/TIGIT checkpoints in the progression of triple-negative breast cancer (TNBC). METHODS: We evaluated CD155 and TIGIT expression in TNBC tissues using both immunohistochemistry (IHC) and gene expression profiling. Our experiments, both in vivo and in vitro, provided evidence that inhibiting the CD155/TIGIT pathway reinstates the ability of CD8 + T cells to generate cytokines. To assess the impact of CD155/TIGIT signaling blockade, we utilized Glucose Assay Kits and Lactate Assay Kits to measure alterations in glucose and lactate levels within CD8 + T cells. We employed western blotting (WB) to investigate alterations in glycolytic-related proteins within the PI3K/AKT/mTOR pathways following the inhibition of CD155/TIGIT signaling. RESULTS: CD155 exhibits heightened expression within TNBC tissues and exhibits a negative correlation with the extent of infiltrating CD8 + T cells. Furthermore, patients with TNBC demonstrate elevated levels of TIGIT expression. Our findings indicate that the interaction between CD155 and TIGIT disrupts the glucose metabolism of CD8 + T cells by suppressing the activation of the PI3K/AKT/mTOR signaling pathway, ultimately leading to the reduced production of cytokines by CD8 + T cells. Both in vivo and in vitro experiments have conclusively demonstrated that the inhibition of CD155/TIGIT interaction reinstates the capacity of CD8 + T cells to generate cytokines. Moreover, in vivo administration of the blocking antibody against TIGIT not only inhibits tumor growth but also augments the functionality of CD8 + T lymphocytes. CONCLUSIONS: Our research findings strongly suggest that CD155/TIGIT represents a promising therapeutic target for treating TNBC.

Synthetic studies on the extracellular domain of the T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) using Trt-K10 solubilizing tags.

The T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is an inhibitory immunoreceptor expressed on lymphocytes that serves as a promising target for cancer immunotherapy. In this study, facile synthetic protocols to produce the extracellular domain of TIGIT were investigated for applications of TIGIT in mirror-image screening. During the synthesis via sequential native chemical ligations, we encountered problems with significantly poor solubility of the ligated products. Introducing trityl-type solubilizing auxiliaries, which also functioned as temporary protecting groups for cysteine residues, facilitated a flexible order of ligations and efficient purification protocols. After refolding under appropriate conditions, the synthetic TIGIT showed a sufficient affinity toward its target ligand CD155.

Astragalus Polysaccharide Alleviates Ulcerative Colitis by Regulating the Balance of mTh17/mTreg Cells through TIGIT/CD155 Signaling.

The balance between memory Th17 cells (mTh17) and memory Treg cells (mTreg) plays a key role in the pathogenesis of ulcerative colitis (UC), and TIGIT signaling is involved in the differentiation of mTh17/mTreg cells. Astragalus polysaccharide (APS) has good immunomodulatory and anti-inflammatory effects. Here, the regulatory effects and potential mechanisms of APS on mTh17/mTreg cells in UC are explored. A UC model was induced with dextran sulfate sodium (DSS) and treated simultaneously with APS (200 mg/kg/day) for 10 days. After APS treatment, the mice showed a significant increase in colonic length and a significant decrease in colonic weight, colonic weight index and colonic weight/colonic length, and more intact mucosa and lighter inflammatory cell infiltration. Notably, APS significantly down-regulated the percentages of Th17 (CD4+CCR6+), cmTh17 (CD4+CCR7+CCR6+) and emTh17 (CD4+CCR7-CCR6+) cells and significantly up-regulated the percentages of cmTreg (CD4+CCR7+Foxp3+) and emTreg (CD4+CCR7-Foxp3+) cells in the mesenteric lymph nodes of the colitis mice. Importantly, APS reversed the expression changes in the TIGIT molecule on mTh17/mTreg cells in the colitis mice with fewer CD4+CCR6+TIGIT+, CD4+CCR7-CCR6+TIGIT+ and CD4+CCR7-CCR6+TIGIT+ cells and more CD4+Foxp3+TIGIT+, CD4+CCR7-Foxp3+TIGIT+ and CD4+CCR7-Foxp3+TIGIT+ cells. Meanwhile, APS significantly inhibited the protein expression of the TIGIT ligands CD155, CD113 and CD112 and downstream proteins PI3K and AKT in the colon tissues of the colitis mice. In conclusion, APS effectively alleviated DSS-induced UC in mice by regulating the balance between mTh17/mTreg cells, which was mainly achieved through regulation of the TIGIT/CD155 signaling pathway.

MicroRNA-326 negatively regulates CD155 expression in lung adenocarcinoma.

Treatment with immune checkpoint inhibitors induces a durable response in some patients with non-small-cell lung cancer, but eventually gives rise to drug resistance. Upregulation of CD155 expression is implicated as one mechanism of resistance to programmed death receptor-1 (PD-1)/PD-1 ligand (PD-L1) inhibitors, and it is therefore important to characterize the mechanisms underlying regulation of CD155 expression in tumor cells. The aim of this study was to identify microRNAs (miRNAs) that might regulate CD155 expression at the posttranscriptional level in lung cancer. Comprehensive miRNA screening with target prediction programs and a dual-luciferase reporter assay identified miR-346, miR-328-3p, miR-326, and miR-330-5p as miRNAs that bind to the 3'-UTR of CD155 mRNA. Forced expression of these miRNAs suppressed CD155 expression in lung cancer cell lines. Immunohistochemical staining of CD155 in tissue specimens from 57 patients with lung adenocarcinoma revealed the median tumor proportion score for CD155 to be 68%. The abundance of miR-326 in these specimens with a low level of CD155 expression was significantly greater than in specimens with a high level (p < 0.005). Our results thus suggest that miR-326 negatively regulates CD155 expression in lung adenocarcinoma and might therefore play a role in the development of resistance to PD-1/PD-L1 inhibitors.

Bispecific anti-CD3×anti-CD155 antibody mediates T-cell immunotherapy in human haematologic malignancies.

T cells are important components in the cell-mediated antitumour response. In recent years, bispecific antibodies (Bi-Abs) have become promising treatments because of their ability to recruit T cells that kill tumours. Here, we demonstrate that CD155 is expressed in a wide range of human haematologic tumours and report on the ability of the bispecific antibody anti-CD3 x anti-CD155 (CD155Bi-Ab) to activate T cells targeting malignant haematologic cells. The specific cytolytic effect of T cells armed with CD155Bi-Ab was evaluated by quantitative luciferase assay, and the results showed that the cytolytic effect of these cells was accompanied by an increase in the level of the cell-killing mediator perforin. Moreover, compared with their unarmed T-cell counterparts, CD155Bi-Ab-armed T cells induced significant cytotoxicity in CD155-positive haematologic tumour cells, as indicated by lactate dehydrogenase assays, and these results were accompanied by increased granzyme B secretion. Furthermore, CD155Bi-Ab-armed T cells produced more T-cell-derived cytokines, including TNF-α, IFN-γ, and IL-2. In conclusion, CD155Bi-Ab enhances the ability of T cells to kill haematologic tumour cells, and therefore, CD155 may serve as a novel target for immunotherapy against haematologic malignancies.

CD96 as a Potential Immune Regulator in Cancers.

The discovery of CTLA-4 and PD-1 checkpoints has prompted scientific researchers and the pharmaceutical industry to develop and conduct extensive research on tumor-specific inhibitors. As a result, the list of potential immune checkpoint molecules is growing over time. Receptors for nectin and nectin-like proteins have recently emerged as promising targets for cancer immunotherapy. Potential immune checkpoints, including CD226, TIGIT, and CD96, belong to this receptor class. Among them, CD96 has received little attention. In this mini-review, we aim to discuss the basic biology of CD96 as well as the most recent relevant research on this as a promising candidate for cancer immunotherapy.

MD Simulation Reveals Regulation of Mechanical Force and Extracellular Domain 2 on Binding of DNAM-1 to CD155.

Two extracellular domains of the adhesive receptor DNAM-1 are involved in various cellular biological processes through binding to ligand CD155, usually under a mechano-microenvironment. The first extracellular domain (D1) plays a key role in recognition, but the function of the second extracellular domain (D2) and effects of force on the interaction of DNAM-1 with CD155 remain unclear. We herein studied the interaction of DNAM-1 with CD155 by performing steered molecular dynamics (MD) simulations, and observed the roles of tensile force and D2 on the affinity of DNAM-1 to CD155. The results showed that D2 improved DNAM-1 affinity to CD155; the DNAM-1/CD155 complex had a high mechanical strength and a better mechanical stability for its conformational conservation either at pulling with constant velocity or under constant tensile force (≤100 pN); the catch-slip bond transition governed CD155 dissociation from DNAM-1; and, together with the newly assigned key residues in the binding site, force-induced conformation changes should be responsible for the mechanical regulation of DNAM-1's affinity to CD155. This work provided a novel insight in understanding the mechanical regulation mechanism and D2 function in the interaction of DNAM-1 with CD155, as well as their molecular basis, relevant transmembrane signaling, and cellular immune responses under a mechano-microenvironment.

CD155 mutation (Ala67Thr) increases the binding affinity for and the signaling via an inhibitory immunoreceptor TIGIT.

CD155 is a shared ligand for activating and inhibitory immunoreceptors DNAX accessory molecule 1 (DNAM-1), also called CD226, and T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT), which are expressed on natural killer (NK) cells and T cells, and positively and negatively regulates tumor immune responses, respectively. A recent study showed that the single nucleotide polymorphism rs1058402G>A causing a mutation to Thr from Ala at residue 67 of CD155 is associated with worse overall survival of patients with small cell lung cancer and suggested that this is caused by the decreased affinity of mutant CD155 for DNAM-1 as a result of the 3D structural analysis. Unexpectedly, however, we found that the mutation increased the binding affinity for TIGIT rather than decreased the binding affinity for DNAM-1 and induced a stronger signal than WT CD155. Our results suggest that the mutation suppresses tumor immune responses by generating a stronger inhibitory signal in immune cells in the tumor microenvironment.

Immune checkpoint CD155 promoter methylation profiling reveals cancer-associated behaviors within breast neoplasia.

BACKGROUND: CD155 immune checkpoint has recently emerged as a compelling immunotherapeutic target. Epigenetic DNA methylation changes are recognized as key molecular mechanisms in cancer development. Hence, the identification of methylation markers that are sensitive and specific for breast cancer may improve early detection and predict prognosis. We speculate that CD155 promoter methylation can be a valuable epigenetic biomarker, based upon strong indications for its immunoregulatory functions. METHODS: Methylation analyses were conducted on 14 CpGs sites in the CD155 promoter region by bisulfite pyrosequencing. To elucidate the related gene expression changes, a transcriptional study using RT-qPCR was performed. Statistical analyses were performed to evaluate correlations of CD155 methylation profiles with mRNA expression together with clinical-pathological features, prognosis and immune infiltrate. RESULTS: CD155 promoter methylation profile was significantly associated with SBR grade, tumor size, molecular subgroups, HER2 and hormonal receptors expression status. Low CD155 methylation rates correlated with better prognosis in univariate cox proportional hazard analysis and appeared as an independent survival predictor in cox-regression multivariate analysis. Further, methylation changes at CD155 specific CpG sites were consistent with CD155 membranous mRNA isoform expression status. Statistical analyses also showed a significant association with immune Natural Killer cell infiltrate when looking at the CpG7, CpG8, CpG9 and CpG11 sites. CONCLUSION: Altogether, our results contribute to a better understanding of the impact of CD155 immune checkpoint modality expression in breast tumors, revealing for the first time that specific CpG sites from CD155 promoter may be a potential biomarker in breast cancer monitoring.

CD155 expression impairs anti-PD1 therapy response in non-small cell lung cancer.

CD155 is an immune checkpoint protein expressed in tumor cells that interacts with its ligand TIGIT, and inhibition of this point presents a new and novel way for cancer therapy. At present, whether the expression of CD155 affects the response to anti(α)-PD1 treatment in non-small cell lung cancer (NSCLC) patients is unclear. This observational study characterizes the expression of CD155 in NSCLC patients and its responses to PD1 inhibitors. We retrospectively detected the expression of CD155 and tumor-infiltrated lymphocyte (TIL) TIGIT by immunohistochemistry in advanced NSCLC patients who had received αPD1 therapy. The patients with CD155 positive had a significantly worse response to αPD1 therapy compared with CD155-negative patients (ORR: 25.6% vs 54.8%, P < 0.01; median PFS: 5.1 vs 7.1 months, HR = 2.322; 95% CI 1.396-3.861, P = 0.001). This effect is more prominent in PD-L1 positive patients. In PD-L1-positive patients, CD155 expression is associated with a poor response to αPD1 therapy in both LUAC (lung adenocarcinoma) and LUSC (lung squamous cell carcinoma); meanwhile, the expression of CD155 was associated with a poor response to the first-line αPD1 therapy, posterior-line αPD1 therapy, and αPD1 combination therapy. Furthermore, the expression of TIGIT was not correlated with the therapeutic effect of αPD1. Our pilot study suggests that CD155 expression attenuates the therapeutic effect of αPD1 therapy and is associated with a higher risk of progression. The CD155 pathway may be a promising immunotherapeutic target and simultaneously targeting CD155/TIGIT and PD1/PD-L1 can improve the effect of immunotherapy.

Blocking TIGIT/CD155 signalling reverses CD8+ T cell exhaustion and enhances the antitumor activity in cervical cancer.

OBJECTIVE: TIGIT/CD155 has attracted widespread attention as a new immune checkpoint and a potential target for cancer immunotherapy. In our study, we evaluated the role of TIGIT/CD155 checkpoints in the progression of cervical cancer. METHODS: The expression of CD155 and TIGIT in cervical cancer tissues was detected using flow cytometry, immunohistochemistry (IHC) and gene expression profiling. In vivo and in vitro experiments have proven that blocking TIGIT/CD155 restores the ability of CD8+ T cells to produce cytokines. Changes in the NF-κB and ERK pathways were detected using western blotting (WB) after blocking TIGIT/CD155 signalling. RESULTS: TIGIT expression was elevated in patients with cervical cancer. High TIGIT expression in CD8+ T lymphocytes from patients with cervical cancer promotes the exhaustion of CD8+ T lymphocytes. In addition, CD155 is expressed at high levels in cervical cancer tissues and is negatively correlated with the level of infiltrating CD8+ T cells. We found that TIGIT, upon binding to CD155 and being phosphorylated, inhibited NF-κB and ERK activation by recruiting SHIP-1, resulting in the downregulation of cytokine production. Blocking TIGIT in activated CD8+ T cells attenuates the inhibitory effect of SHIP-1 on CD8+ T cells and enhances the activation of NF-κB and ERK. In vivo and in vitro experiments have proven that blocking TIGIT/CD155 restores the ability of CD8+ T cells to produce cytokines. Injecting the blocking antibody TIGIT in vivo inhibits tumour growth and enhances CD8+ T lymphocyte function. Treatment with a combination of TIGIT and PD-1 inhibitors further increases the efficacy of the TIGIT blocking antibody. CONCLUSIONS: Our research shows that TIGIT/CD155 is a potential therapeutic target for cervical cancer.

DNAM-1 versus TIGIT: competitive roles in tumor immunity and inflammatory responses.

The co-stimulatory and co-inhibitory immunoreceptors, DNAX accessory molecule-1 (DNAM-1) and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT), are paired activating and inhibitory receptors on T cells and natural killer (NK) cells. They share the ligands poliovirus receptor (PVR, CD155) and its family member nectin-2 (CD112), which are highly expressed on antigen-presenting cells (APCs), tumors and virus-infected cells. Upon ligation with the ligands, DNAM-1 and TIGIT show reciprocal functions; whereas DNAM-1 promotes activation, proliferation, cytokine production and cytotoxic activity in effector lymphocytes, including CD4+ T-helper cells, CD8+ cytotoxic T lymphocytes and NK cells, TIGIT inhibits these DNAM-1 functions. On the other hand, DNAM-1 competes with TIGIT on regulatory T (Treg) cells in binding to CD155 and therefore regulates TIGIT signaling to down-regulate Treg cell function. Thus, whereas DNAM-1 enhances anti-tumor immunity and inflammatory responses by augmenting effector lymphocyte function and suppressing Treg cell function, TIGIT reciprocally suppresses these immune responses by suppressing effector lymphocyte function and augmenting Treg cell function. Thus, blockade of DNAM-1 and TIGIT function would be potential therapeutic approaches for patients with inflammatory diseases and those with cancers and virus infection, respectively.

TIGIT and CD155 as Immune-Modulator Receptor and Ligand on CD4+ T cells in Preeclampsia Patients.

One of the main characteristics of preeclampsia (PE) is systemic inflammation. CD4+ FoxP3+ cells play a critical role in both fetomaternal tolerance and successful pregnancy. T-cell immunoglobulin, as well as immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT)/CD155 pathway, possesses critical parts in the development of normal pregnancy by promoting regulatory T (Treg) cells. However, in PE, the relationship between TIGIT/CD155 and Treg differentiation has not been entirely clarified. In the current report, we aimed to assess the frequency of TIGIT and CD155 expressing TCD4+ cells in both PE and healthy pregnant women, as well as evaluating the amount of inflammatory and inhibitory cytokines at both mRNA and protein levels before and after blocking TIGIT and CD155. In the present report, 59 healthy, and 52 PE patients were designated to obtain their venous blood. The isolation of peripheral blood mononuclear cells (PBMCs) was performed from the blood samples, and PBMCs were then cultured in the RPMI1640 medium. The percentage of CD155+ and TIGIT+ CD4+ cells was assessed by flow cytometry in PBMCs. Cell culture supernatants were utilized to evaluate the secretory levels of transforming growth factor beta (TGF-ß), interleukin (IL)-10, IL-17, tumor necrosis factor alpha (TNF-α), and IL-1 ß, using enzyme-linked immunosorbent assay technique in pregnant women with or without PE both before and after blocking TIGIT and CD155. The mRNA expression of Foxp3, TIGIT, CD155, SHP-1, TGF-ß, IL-10, IL-17, TNF-α, and IL-1ß was also assessed by qRT-PCR in PBMCs before and after blocking TIGIT and CD155 in both populations. The data showed a significant decrease in the frequency of TIGIT+ CD4+ and CD155+ CD4+ T cells in PE women, compared to the control group. Our results showed decreased protein and mRNA levels of TIGIT, CD155, IL-10, FOXP3, and SHP-1 in PE patients. In addition, significant improvements in the levels of IL-17, TNF-α, and IL-1ß were observed in PE patients, as compared with the controls. However, blocking TIGIT and CD155 could increase these inflammatory cytokines and decrease anti-inflammatory cytokines. The data obtained in this report illustrated that there existed an imbalance between inflammatory and anti-inflammatory profiles, with an inflammatory status polarization, in PE patients. Additionally, TIGIT/CD155 showed a positive effect on immune regulation by activating ITIM, demonstrating the potential therapeutic value of the TIGIT/CD155 pathway in PE treatment. Also, using some proteins or materials that increased TIGIT/CD155 pathways activity and can be a therapeutic approach in PE.

CD155/TIGIT signaling regulates the effector function of tumor-infiltrating CD8+ T cell by NF-κB pathway in colorectal cancer.

BACKGROUND AND AIM: CD155/T-cell immunoglobulin and ITIM domain (TIGIT) suppressed anti-cancer immunity in several cancers, but its roles in colorectal cancer (CRC) were not clear. Here, we investigated its roles in CRC. METHODS: The percentages of CD8+ T cells expressing TIGIT and secreting cytokines (IL-2, TNF-α, and IFNγ) were evaluated by flow cytometry. The expression level of CD155 was determined by western blot and immunohistochemistry. The levels of cytokines were determined by enzyme-linked immunosorbent assay. The activation of the nuclear factor-kappa B (NF-κB) pathway was examined by western blot and immunofluorescent assay. RESULTS: T-cell immunoglobulin and ITIM domain was overexpressed on CD8+ T cells of CRC patients and mice. CD155 was overexpressed in mice CRC tissues and cells. The addition of CD155 recombinant protein could decrease the percentages of CD8+ T cells secreting cytokines. Blocking TIGIT could increase the percentages of cytokine-secreting CD8+ T cells. Coculturing with CD155-knockdown CRC cells could upregulate the percentages of CD8+ T cells secreting cytokines. Blocking TIGIT partially counteracted the effect of the knockdown of CD155. Besides, coculturing with CD155-knockdown CRC cells could promote the secretion of cytokines, activate the NF-κB pathway, and enhance the nuclear translocation of p65. And these effects were counteracted by the application of an NF-κB inhibitor. Finally, blocking TIGIT played anti-cancer roles such as suppression of tumor growth, increasing the percentages of cytokine-secreting CD8+ T cells and activation of the NF-κB signaling pathway. CONCLUSION: Suppressing CD155/TIGIT exerted anti-cancer effects against CRC, and our findings provided a potential therapeutic approach to treat CRC.

Prognostic and clinicopathological significance of CD155 expression in cancer patients: a meta-analysis.

BACKGROUND: It has been previously reported that CD155 is often over-expressed in a variety of cancer types. In fact, it is known to be involved in cancer development, and its role in cancer has been widely established. However, clinical and mechanistic studies involving CD155 yielded conflicting results. Thus, the present study aimed to evaluate overall prognostic value of CD155 in cancer patients, using a comprehensive analysis. METHODS: Online databases were searched, data was collected, and clinical value of CD155 was evaluated by combining hazard ratios (HRs) or odds ratios (ORs). RESULTS: The present study involved meta-analysis of 26 previous studies that involved 4325 cancer patients. These studies were obtained from 25 research articles. The results of the study revealed that increased CD155 expression was significantly associated with reduced OS in patients with cancer as compared to low CD155 expression (pooled HR = 1.772, 95% CI = 1.441-2.178, P < 0.001). Furthermore, subgroup analysis demonstrated that the level of CD155 expression was significantly associated with OS in patients with digestive system cancer (pooled HR = 1.570, 95% CI = 1.120-2.201, P = 0.009), hepatobiliary pancreatic cancer (pooled HR = 1.677, 95% CI = 1.037-2.712, P = 0.035), digestive tract cancer (pooled HR = 1.512, 95% CI = 1.016-2.250, P = 0.042), breast cancer (pooled HR = 2.137, 95% CI = 1.448-3.154, P < 0.001), lung cancer (pooled HR = 1.706, 95% CI = 1.193-2.440, P = 0.003), head and neck cancer (pooled HR = 1.470, 95% CI = 1.160-1.862, P = 0.001). Additionally, a significant correlation was observed between enhanced CD155 expression and advanced tumor stage (pooled OR = 1.697, 95% CI = 1.217-2.366, P = 0.002), LN metastasis (pooled OR = 1.953, 95% CI = 1.253-3.046, P = 0.003), and distant metastasis (pooled OR = 2.253, 95% CI = 1.235-4.110, P = 0.008). CONCLUSION: Altogether, the results of the present study revealed that CD155 acted as an independent marker of prognosis in cancer patients, and it could provide a new and strong direction for cancer treatment.

Examination of the TIGIT-CD226-CD112-CD155 Immune Checkpoint Network during a Healthy Pregnancy.

Background: The importance of immune checkpoint molecules is well known in tumor and transplantation immunology; however, much less information is available regarding human pregnancy. Despite the significant amount of information about the TIGIT and CD226 immune checkpoint receptors in immune therapies, very little research has been conducted to study the possible role of these surface molecules and their ligands (CD112 and CD155) during the three trimesters of pregnancy. Methods: From peripheral blood, immune cell subpopulations were studied, and the surface expression of immune checkpoint molecules was analyzed by flow cytometry. Soluble immune checkpoint molecule levels were measured by ELISA. Results: Notable changes were observed regarding the percentage of monocyte subpopulation and the expression of CD226 receptor by CD4+ T and NKT cells. Elevated granzyme B content by the intermediate and non-classical monocytes was assessed as pregnancy proceeded. Furthermore, we revealed an important relationship between the CD226 surface expression by NKT cells and the serum CD226 level in the third trimester of pregnancy. Conclusions: Our results confirm the importance of immune checkpoint molecules in immunoregulation during pregnancy. CD226 seems to be a significant regulator, especially in the case of CD4+ T and NKT cells, contributing to the maternal immune tolerance in the late phase of pregnancy.