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Natural killer (NK) cells are lymphocytes of the innate immune response characterized by their role in the destruction of tumor cells. Activation of NK cells depend on a fine balance between activating and inhibitory signals mediated by different receptors. In recent years, a family of paired receptors that interact with ligands of the Nectin/Nectin-like (Necl) family has attracted great interest. Two of these ligands, Necl-5 (usually termed CD155 or PVR) and Nectin-2 (CD112), frequently expressed on different types of tumor cells, are recognized by a group of receptors expressed on T and NK cells that exert opposite functions after interacting with their ligands. These receptors include DNAM-1 (CD226), TIGIT, TACTILE (CD96) and the recently described PVRIG. Whereas activation through DNAM-1 after recognition of CD155 or CD112 enhances NK cell-mediated cytotoxicity against a wide range of tumor cells, TIGIT recognition of these ligands exerts an inhibitory effect on NK cells by diminishing IFN-γ production, as well as NK cell-mediated cytotoxicity. PVRIG has also been identified as an inhibitory receptor that recognizes CD112 but not CD155. However, little is known about the role of TACTILE as modulator of immune responses in humans. TACTILE control of tumor growth and metastases has been reported in murine models, and it has been suggested that it negatively regulates the anti-tumor functions mediated by DNAM-1. In NK cells from patients with solid cancer and leukemia, it has been observed a decreased expression of DNAM-1 that may shift the balance in favor to the inhibitory receptors TIGIT or PVRIG, further contributing to the diminished NK cell-mediated cytotoxic capacity observed in these patients. Analysis of DNAM-1, TIGIT, TACTILE and PVRIG on human NK cells from solid cancer or leukemia patients will clarify the role of these receptors in cancer surveillance. Overall, it can be speculated that in cancer patients the TIGIT/PVRIG pathways are upregulated and represent novel targets for checkpoint blockade immunotherapy.

Natural killer (NK) cells are powerful immune effectors, modulating their anti-tumor function through a balance activating and inhibitor ligands on their cell surface. Though still emerging, cancer immunotherapies utilizing NK cells are proving promising as a modality for the treatment of a number of solid tumors, including glioblastoma (GBM) and other gliomas, but are often limited due to complex immunosuppression associated with the GBM tumor microenvironment which includes overexpression of inhibitory receptors on GBM cells. CD155, or poliovirus receptor (PVR), has recently emerged as a pro-tumorigenic antigen, overexpressed on GBM and contributing to increased GBM migration and aggressiveness. CD155 has also been established as an immunomodulatory receptor, able to both activate NK cells through interactions with CD226 (DNAM-1) and CD96 and inhibit them through interaction with TIGIT. However, NK cell TIGIT expression has been shown to be upregulated in cancer, establishing CD155 as a predominantly inhibitory receptor within the context of GBM and other solid tumors, and rendering it of interest as a potential target for antigen-specific NK cell-based immunotherapy. This review will explore the function of CD155 within GBM as it relates to tumor migration and NK cell immunoregulation, as well as pre-clinical and clinical targeting of CD155/TIGIT and the potential that this pathway holds for the development of emerging NK cell-based immunotherapies.

T cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory receptor expressed on several types of lymphocytes. Efficacy of antibody blockade of TIGIT in cancer immunotherapy is currently widely being investigated in both pre-clinical and clinical studies. In multiple cancers TIGIT is expressed on tumor-infiltrating cytotoxic T cells, helper T cells, regulatory T cells and NK cells, and its main ligand CD155 is expressed on tumor-infiltrating myeloid cells and upregulated on cancer cells, which contributes to local suppression of immune-surveillance. While single TIGIT blockade has limited anti-tumor efficacy, pre-clinical studies indicate that co-blockade of TIGIT and PD-1/PD-L1 pathway leads to tumor rejection, notably even in anti-PD-1 resistant tumor models. Among inhibitory immune checkpoint molecules, a unique property of TIGIT blockade is that it enhances not only anti-tumor effector T-cell responses, but also NK-cell responses, and reduces the suppressive capacity of regulatory T cells. Numerous clinical trials on TIGIT-blockade in cancer have recently been initiated, predominantly combination treatments. The first interim results show promise for combined TIGIT and PD-L1 co-blockade in solid cancer patients. In this review, we summarize the current knowledge and identify the gaps in our current understanding of TIGIT’s roles in cancer immunity, and provide, based on these insights, recommendations for its positioning in cancer immunotherapy.

T cell immunoreceptor with Ig and ITIM domains (TIGIT) interacts with poliovirus receptor (PVR) to contribute to cancer immune escape. Recently, TIGIT and PVR have been identified as promising immunotherapy targets. Their gene expression is upregulated in many solid tumors, but their protein expression level is not well documented, particularly in triple negative breast cancer (TNBC), the breast cancer subtype that most benefit from immunotherapy. TIGIT and PVR expression levels were assessed by immunohistochemistry in 243 surgically resected localized TNBC and then their relationship with clinical-pathological features and clinical outcome was analyzed. TIGIT expression was observed in immune cells from the tumor microenvironment, whereas PVR was mainly expressed by tumor cells. High TIGIT expression was significantly associated with age (p=0.010), histological grade (p=0.014), non-lobular histology (p=0.024), adjuvant chemotherapy (p=0.006), and various immune cell populations (tumor infiltrating lymphocytes (TILs), CD3 , CD8 , PD-1 cells; all p<0.0001), PD-L1 tumor cells (p<0.0001), and PD-L1 stromal cells (p=0.003). Infiltration by TIGIT cells tended to be higher in non-molecular apocrine tumors (p=0.088). PVR was significantly associated with histological grade (p<0.0001), the basal-like (p=0.003) and non-molecular apocrine phenotypes (p=0.039), high TILs infiltration (p=0.011), CD3 (p=0.002), CD8 (p=0.024) T cells, and PD-L1 expression in tumor (p=0.003) and stromal cells (p=0.001). In univariate analysis, only known prognostic factors (age, tumor size, lymph node status, adjuvant chemotherapy, TILs and CD3 T-cell infiltrate) were significantly associated with relapse-free survival (RFS) and overall survival. High TIGIT and PVR expression levels tended to be associated with longer RFS (p=0.079 and 0.045, respectively). The analysis that included only non-molecular apocrine TNBC revealed longer RFS for tumors that strongly expressed TIGIT or PVR (p=0.025 for TIGIT and 0.032 for PVR). These results indicated that in TNBC, TIGIT cells can easily interact with PVR to exert their inhibitory effects. Their wide expression in TNBC and their association with other immune checkpoint components suggest the therapeutic interest of the TIGIT-PVR axis.

Background Exploring novel therapeutic targets and developing targeted therapies constitute an urgent clinical need for improving the prognosis of ovarian cancer (OC), particularly among patients with advanced stages. Currently, chimeric antigen receptor T (CAR-T) cell therapy has been demonstrated to have a remarkable therapeutic effect in hematological malignancies, while its application remains limited in OC due to the absence of appropriate target molecules and the complex immunosuppressive tumor microenvironment (TME). Poliovirus receptor (PVR, CD155) has been the subject of extensive research in the field of regulatory molecules within the immune microenvironment. However, there has been a paucity of research investigating its role in OC. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is barely expressed in normal tissues but widely expressed in tumor tissues, making it a promising target for CAR-T therapy. Nevertheless, the potential effectiveness of CAR-T cell targeting ROR1 in OC remains unknown. Therefore, the purpose of this study is twofold: The primary objective of this study is to investigate the potential efficacy of single-target ROR1-CAR-T cells on OC. The secondary objective is to examine the feasibility of CD155 as an immunotherapy target for OC and to determine whether combined targeting of CD155 can enhance the function of ROR1-CAR-T cells in OC. Method ROR1 and CD155 expression were detected via flow cytometry analysis. In vitro experiments were conducted to explore the regulatory effect of CD155 on OC proliferation, invasion, angiogenesis, and T cell function. ROR1-CAR, CD155-CAR, and ROR1/CD155 bispecific CAR constructs were designed and synthesized. Then, they were introduced into T cells using lentiviral particles to generate CAR-T cells. We subsequently validated the synergistic effects of CD155 in ROR1/CD155 bispecific CAR-T cells based on cytotoxic efficacy, activation, exhaustion, and differentiation status. Results ROR1-CAR-T cells exhibited tumoricidal activity in OC, but elevated tonic signaling was observed, resulting in rapid depletion. CD155 constitutes an ideal therapeutic target in OC: firstly, ubiquitous CD155 expression in OC cell lines. Secondly, CD155 promotes tumor proliferation, migration, and angiogenesis in OC cell lines, acting as an oncogenic driver. Thirdly, CD155 impairs T cell function and accelerates their depletion, contributing to an immunosuppressive TME. The bispecific CAR-T combined targeting CD155 and ROR1 demonstrated superior cytotoxicity compared to single-target ROR1-CAR-T or CD155-CAR-T. Co-targeting CD155 significantly attenuated tonic signaling and delayed CAR-T cell exhaustion. Conclusion CD155 emerges as a promising therapeutic target for CAR-T therapy in OC. The bispecific CAR-T construct that co-targets CD155 and ROR1 demonstrates superior and durable tumoricidal activity, offering new perspectives on OC targeted therapy.

CD155 is the fifth member in the nectin‐like molecule family, and functions as the receptor of poliovirus; therefore, CD155 is also referred to as necl‐5, or PVR. As an immunoglobulin‐like adhesion molecule, CD155 is involved in cell motility, and natural killer and T cell‐mediated immunity. CD155 is barely or weakly expressed in various normal human tissues, but frequently overexpressed in human malignant tumors. CD155 overexpression promotes tumor cell invasion and migration, and is associated with tumor progression and poor prognosis. As the ligand for both costimulatory receptor CD226 and coinhibitory receptor TIGIT and CD96 on natural killer and T cells, CD155 seems to play a dual role in oncoimmunity. However, some recent studies indicate that CD155 overexpression may induce tumor immune escape. Taken together, CD155 may be considered as a target for the treatment of tumors with CD155 overexpression. CD155 overexpression promotes tumor cell invasion and migration, and is associated with tumor progression and poor prognosis. As the ligand for both costimulatory receptor CD226 and coinhibitory receptor TIGIT and CD96 on NK and T cells, CD155 seems to play a dual role in oncoimmunity. Some recent studies indicate that CD155 overexpression may induce tumor immune escape.

Treatment strategies for patients with advanced solid tumors have traditionally been based on three different paradigms: surgery, cytotoxics (chemotherapy or radiation therapy) and targeted therapies. Immunotherapy has emerged as a novel treatment paradigm in our armamentarium. Unfortunately, most patients still do not benefit from immunotherapy. These patients often have “cold tumors” characterized by a paucity of effector T cells in the tumor microenvironment, low mutational load, low neoantigen burden and often an immunosuppressive tumor microenvironment. TIGIT is an immunoreceptor inhibitory checkpoint that has been implicated in tumor immunosurveillance. Expression of TIGIT has been demonstrated in both NK cells and T cells and plays a role in their activation and maturation. TIGIT competes with immunoactivator receptor CD226 (DNAM-1) for the same set of ligands: CD155 (PVR or poliovirus receptor) and CD112 (Nectin-2 or PVRL2). TIGIT’s role in tumor immunosurveillance is analogous to the PD-1/PD-L1 axis in tumor immunosuppression. Both TIGIT and PD-1 are upregulated in a variety of different cancers. Anti-TIGIT antibodies have demonstrated synergy with anti-PD-1/PD-L1 antibodies in pre-clinical models. Currently, there are multiple first-in-man phase I trials hoping to exploit this new pathway and improve response rates with existing immunotherapies.

BackgroundAcute-on-chronic liver failure (ACLF) is a syndrome characterised by multiple organ failure and high short-term mortality. The condition represents an immunological paradox in that rampant systemic inflammation, which drives organ dysfunction, exists alongside immune cell dysfunction and increased susceptibility to bacterial infections. Understanding the mechanisms that control this balance is therefore critical.CD96 is an immune checkpoint expressed on T cells and NK cells that transmits an inhibitory signal when bound to its ligand CD155 (PVR). Both CD96 and CD155 have soluble forms, with elevated concentrations found in other immunosuppressive states such as cancer and chronic viral infections. In this study we explored the CD96-CD155 immune checkpoint axis in patients with ACLF.MethodThe expression of membrane bound CD96 on peripheral lymphoid cells was assessed by flow cytometry in patients with acute decompensated cirrhosis (AD) and ACLF, compared to healthy controls (HC) (n = 8 per group). In a separate cohort, concentrations of plasma soluble CD96 and CD155 in patients with AD (n = 8) or ACLF (n = 23), compared to HC (n = 8), was determined with a Luminex multiplex assay.ResultsCD4+ T cells from patients with ACLF had increased expression of CD96 than those from HC (46.69 versus 14.04%, p = 0.02, figure 1A) and sCD96 concentrations were higher in ACLF than HC (1541 versus 563.6pg/ml, p = 0.01, figure 1B). sCD96 concentration correlated positively with Child Pugh Score (r = 0.43, p = 0.02) and was higher in ACLF non-survivors at 1 month than survivors (2245 versus 1100 pg/ml, p = 0.01, figure 1C). sCD155 concentrations were also increased in ACLF compared to HC (8875 versus 2686pg/ml, p = 0.01).Abstract P44 Figure 1ConclusionExpression of the inhibitory immune checkpoint CD96 is increased on CD4+ T cells in ACLF patients and this is mirrored by higher plasma sCD96 concentrations. The latter correlates with cirrhosis disease severity and is higher in ACLF non-survivors. CD96 could therefore be an immunomodulatory target in ACLF, and sCD96 a useful prognostic marker.

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 ( K _ ras , M _ yc , F _ AK ) 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.

Recent studies have shown that aberrant expression of tight junction proteins (TJP) contributes to malignant potential of various cancers. In the present study, we investigated the expression of junctional adhesion molecule‐A (JAM‐A), one of the transmembrane TJP, in uterine cervical adenocarcinoma and the significance of its expression for malignancy. Immunohistochemistry on human surgical specimens showed that JAM‐A was aberrantly expressed in neoplastic regions including adenocarcinoma in situ (AIS). Knockout of JAM‐A significantly suppressed cell proliferation and colony‐forming and migration abilities. We also showed that an antibody specific to an extracellular region of JAM‐A reduced cell proliferation ability and that loss of JAM‐A increased drug sensitivity of cervical adenocarcinoma cells. Based on a comprehensive proteome analysis, we found that poliovirus receptor (PVR/CD155) was regulated by JAM‐A and formed a physical interaction with JAM‐A. In human surgical specimens, PVR/CD155 expression was significantly correlated with some clinicopathological features and prognosis of cervical adenocarcinoma. Interestingly, most of the PVR/CD155‐positive cases expressed a high level of JAM‐A, and patients with the expression pattern of PVR/CD155 positive/JAM‐A high had significantly shorter periods of relapse‐free survival (P = .00964) and overall survival (P = .0204) than those for the other patients. Our observations suggest that aberrant expression of JAM‐A promotes malignancy of uterine cervical adenocarcinoma by regulation of PVR/CD155, and JAM‐A is therefore a potential therapeutic target for this malignancy. Aberrant expression of junctional adhesion molecule‐A (JAM‐A), one of the transmembrane tight junction proteins, contributes to the malignant potential of uterine cervical adenocarcinoma. We also show that loss of JAM‐A attenuated drug resistance of cervical adenocarcinoma cells and that an anti‐JAM‐A antibody inhibited cell proliferation, indicating that JAM‐A is a potential therapeutic target of the malignancy. Moreover, we show that a novel interaction between JAM‐A and poliovirus receptor (PVR/CD155) is associated with worse prognosis of cervical adenocarcinoma.