Melanoma Cells Control Antimelanoma CTL Responses via Interaction between TIGIT and CD155 in the Effector Phase

Inozume, Takashi; Yaguchi, Tomonori; Furuta, Junpei; Harada, Kazutoshi; Kawakami, Yutaka; Shimada, Shinji

doi:10.1038/jid.2015.404

Cited by 149 publications

(136 citation statements)

References 30 publications

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“…Melanoma cells suppress T-cell responses through CD155-TIGIT interactions (16). To investigate whether CD155 is involved in the inhibition on T cells mediated by gastric cancer cells, we tested CD155 expression on gastric cancer tissue and gastric cancer cell lines.…”

Section: Gastric Cancer Cells Inhibit T-cell Metabolism Through Cd155mentioning

confidence: 99%

“…Blocking TIGIT enhances CD8 T-cell effector functions in tumor-bearing mice (15). In addition, CD155 expression is increased in melanoma cells, and the T-cell response is inhibited via TIGIT À CD155 interactions (16). However, the mechanisms of CD155/TIGITinduced immune suppression and subversion in gastric cancer remain poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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CD155T/TIGIT Signaling Regulates CD8+ T-cell Metabolism and Promotes Tumor Progression in Human Gastric Cancer

et al. 2017

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The T-cell surface molecule TIGIT is an immune checkpoint molecule that inhibits T-cell responses, but its roles in cancer are little understood. In this study, we evaluated the role TIGIT checkpoint plays in the development and progression of gastric cancer. We show that the percentage of CD8 T cells that are TIGIT þ was increased in gastric cancer patients compared with healthy individuals. These cells showed functional exhaustion with impaired activation, proliferation, cytokine production, and metabolism, all of which were rescued by glucose. In addition, gastric cancer tissue and cell lines expressed CD155, which bound TIGIT receptors and inactivated CD8 T cells. In a T cell-gastric cancer cell coculture system, gastric cancer cells deprived CD8 T cells of glucose and impaired CD8 T-cell effector functions; these effects were neutralized by the additional glucose or by TIGIT blockade. In gastric cancer tumor cells, CD155 silencing increased T-cell metabolism and IFNg production, whereas CD155 overexpression inhibited T-cell metabolism and IFNg production; this inhibition was neutralized by TIGIT blockade. Targeting CD155/TIGIT enhanced CD8 T-cell reaction and improved survival in tumor-bearing mice. Combined targeting of TIGIT and PD-1 further enhanced CD8 T-cell activation and improved survival in tumor-bearing mice.Our results suggest that gastric cancer cells inhibit CD8 T-cell metabolism through CD155/TIGIT signaling, which inhibits CD8 T-cell effector functions, resulting in hyporesponsive antitumor immunity. These findings support the candidacy of CD155/TIGIT as a potential therapeutic target in gastric cancer.

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Section: Gastric Cancer Cells Inhibit T-cell Metabolism Through Cd155mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CD155T/TIGIT Signaling Regulates CD8+ T-cell Metabolism and Promotes Tumor Progression in Human Gastric Cancer

et al. 2017

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“…Engagement of TIGIT with CD155 competes with the interaction between the activating receptor DNAM-1 and CD155, resulting in decreased NK cell cytolytic activity and IFNγ production (16,18). Recently, TIGIT was found to be highly expressed on tumor-infiltrating lymphocytes (TILs), and co-blockade of TIGIT and PD-1 synergistically augmented CD8 + T cell activity against autologous tumor cells (19). TIGIT is also expressed on polyclonal NK cells (20), but little is known with respect to how TIGIT regulates human NK cell function in the tumor microenvironment.…”

Section: Introductionmentioning

confidence: 99%

Adaptive NK Cells with Low TIGIT Expression Are Inherently Resistant to Myeloid-Derived Suppressor Cells

et al. 2016

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Human cytomegalovirus (CMV)-induced adaptive natural killer (NK) cells display distinct phenotypic and functional characteristics, including properties of immune memory. We hypothesized that these cells may be more resistant to suppression mediated by immune regulatory cell subsets, making them attractive for use in cancer therapy. Here we report that relative to conventional NK cells, adaptive NK cells express lower levels of the inhibitory receptor TIGIT which results in resistance to immune suppression mediated by myeloid-derived suppressor cells (MDSC), as derived from cytokine induction in normal blood or patients with myelodysplastic syndrome (MDS). In contrast, conventional NK cells were potently suppressed by MDSC, an effect abrogated completely by TIGIT blockade. Mechanistically, TIGIT signaling in NK cells after MDSC co-culture led to a decrease in the phosphorylation of ZAP70/Syk and ERK1/2. These effects were reversed by blocking TIGIT on NK cells or by inhibiting production of reactive oxygen species (ROS) by MDSC, the latter of which upregulated the TIGIT ligand CD155 on MDSC. Accordingly, the blunted cytotoxicity of NK cells co-cultured with MDSC against tumor cells could be reversed by blocking TIGIT or ROS production. Overall, our results show how adaptive NK cells arising in response to CMV infection can escape MDSC-mediated suppression, and defined TIGIT antagonists as a novel type of checkpoint inhibitor to enhance NK cell-mediated responses against cancer and infection.

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“…Utilizing the unfolded protein response (UPR), HCC reduces PVR expression, lessening the probability that NK cells will detect and destroy the cancerous cells (Gong et al, 2014). Alternatively, melanoma cells manipulate the expression of TIGIT on CTLs to convert PVR into an immunosuppressive agent (Inozume et al, 2016; Pauken and Wherry, 2014; Stanietsky et al, 2009). In the presence of IFNγ + melanoma tumors, CTL cells experience CD226 suppression and TIGIT activation (Lozano et al, 2012).…”

Section: Pvr and Cancermentioning

confidence: 99%

“…In the presence of IFNγ + melanoma tumors, CTL cells experience CD226 suppression and TIGIT activation (Lozano et al, 2012). Increased TIGIT expression on CTLs combined with enhanced PVR expression on melanoma cells leads to the suppression of the cell mediated immune response, thus facilitating the progression of the melanoma tumor (Chauvin et al, 2015; Inozume et al, 2016). …”

Section: Pvr and Cancermentioning

confidence: 99%

Poliovirus Receptor: More than a simple viral receptor

et al. 2017

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The human poliovirus receptor (PVR) is a cell surface protein with a multitude of functions in human biology. PVR was initially identified as the receptor for the human poliovirus and recent discoveries have given a greater insight into both its morphology and its function. Alternative splicing of the PVR gene results in a total of 4 alternatively spliced isoforms. Two of these isoforms lack a complete transmembrane domain and are considered soluble and block viral infection; the remaining two transmembrane isoforms differ only at their extreme C-terminal domains resulting in differential localization in epithelia and polarity of viral infection. In addition to its role as a receptor for the human poliovirus, several native biological functions have also been uncovered. PVR is an important cell adhesion protein and is involved in the transendothelial migration of leukocytes. Through its interactions with CD226 and TIGIT, transmembrane proteins found on leukocytes, PVR is a key regulator of the cell-mediated immune response. As PVR is differentially regulated in a broad spectrum of cancers, it has a strong potential for clinical use as a biomarker. PVR is also a possible target for novel cancer therapies. Utilizing its natural tropism for PVR, a genetically modified form of the live attenuated poliovirus vaccine is currently being tested for its ability to locate and destroy certain tumors. These recent studies emphasize the importance of PVR in human biology and demonstrate its utility beyond being a viral receptor protein.

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Melanoma Cells Control Antimelanoma CTL Responses via Interaction between TIGIT and CD155 in the Effector Phase

Cited by 149 publications

References 30 publications

CD155T/TIGIT Signaling Regulates CD8+ T-cell Metabolism and Promotes Tumor Progression in Human Gastric Cancer

CD155T/TIGIT Signaling Regulates CD8+ T-cell Metabolism and Promotes Tumor Progression in Human Gastric Cancer

Adaptive NK Cells with Low TIGIT Expression Are Inherently Resistant to Myeloid-Derived Suppressor Cells

Poliovirus Receptor: More than a simple viral receptor

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