The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Nicole Joller - One of the best experts on this subject based on the ideXlab platform.
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tim 3 lag 3 and TIGIT
Current Topics in Microbiology and Immunology, 2017Co-Authors: Nicole Joller, Vijay K KuchrooAbstract:Co-inhibitory receptors play a key role in regulating T cell responses and maintaining immune homeostasis. Their inhibitory function prevents autoimmune responses but also restricts the ability of T cells to mount effective immune responses against tumors or persistent pathogens. T cells express a module of co-inhibitory receptors, which display great diversity in expression, structure, and function. Here, we focus on the co-inhibitory receptors Tim-3, Lag-3, and TIGIT and how they regulate T cell function, maintenance of self-tolerance, their role in regulating ongoing T cell responses at peripheral tissues, and their synergistic effects in regulating autoimmunity and antitumor responses.
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TIGIT predominantly regulates the immune response via regulatory t cells
Journal of Clinical Investigation, 2015Co-Authors: Sema Kurtulus, Nicole Joller, Kaori Sakuishi, Shin Foong Ngiow, Dewar J Tan, Michele W L Teng, Mark J SmythAbstract:Coinhibitory receptors are critical for the maintenance of immune homeostasis. Upregulation of these receptors on effector T cells terminates T cell responses, while their expression on Tregs promotes their suppressor function. Understanding the function of coinhibitory receptors in effector T cells and Tregs is crucial, as therapies that target coinhibitory receptors are currently at the forefront of treatment strategies for cancer and other chronic diseases. T cell Ig and ITIM domain (TIGIT) is a recently identified coinhibitory receptor that is found on the surface of a variety of lymphoid cells, and its role in immune regulation is just beginning to be elucidated. We examined TIGIT-mediated immune regulation in different murine cancer models and determined that TIGIT marks the most dysfunctional subset of CD8+ T cells in tumor tissue as well as tumor-tissue Tregs with a highly active and suppressive phenotype. We demonstrated that TIGIT signaling in Tregs directs their phenotype and that TIGIT primarily suppresses antitumor immunity via Tregs and not CD8+ T cells. Moreover, TIGIT+ Tregs upregulated expression of the coinhibitory receptor TIM-3 in tumor tissue, and TIM-3 and TIGIT synergized to suppress antitumor immune responses. Our findings provide mechanistic insight into how TIGIT regulates immune responses in chronic disease settings.
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mechanisms of TIGIT driven immune suppression in cancer
Journal for ImmunoTherapy of Cancer, 2014Co-Authors: Sema Kurtulus, Nicole Joller, Vijay K Kuchroo, Kaori Sakuishi, Dewar J Tan, Mark J Smyth, Huiyuan Zhang, Ana C AndersonAbstract:Meeting abstracts TIGIT is a co-inhibitory molecule that limits T cell proliferation and activation. TIGIT expression has been recently shown to identify a subset of regulatory T cells (Treg) that specifically suppresses Th1 and Th17 responses; however its role in tumor immunity has not been
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treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory th1 and th17 cell responses
Immunity, 2014Co-Authors: Nicole Joller, Sheng Xiao, Ester Lozano, Patrick R Burkett, Bonny Patel, Chen Zhu, Junrong Xia, Tze Guan Tan, Esen Sefik, Vijay YajnikAbstract:Foxp3(+) T regulatory (Treg) cells regulate immune responses and maintain self-tolerance. Recent work shows that Treg cells are comprised of many subpopulations with specialized regulatory functions. Here we identified Foxp3(+) T cells expressing the coinhibitory molecule TIGIT as a distinct Treg cell subset that specifically suppresses proinflammatory T helper 1 (Th1) and Th17 cell, but not Th2 cell responses. Transcriptional profiling characterized TIGIT(+) Treg cells as an activated Treg cell subset with high expression of Treg signature genes. Ligation of TIGIT on Treg cells induced expression of the effector molecule fibrinogen-like protein 2 (Fgl2), which promoted Treg-cell-mediated suppression of T effector cell proliferation. In addition, Fgl2 was necessary to prevent suppression of Th2 cytokine production in a model of allergic airway inflammation. TIGIT expression therefore identifies a Treg cell subset that demonstrates selectivity for suppression of Th1 and Th17 cell but not Th2 cell responses.
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cutting edge TIGIT has t cell intrinsic inhibitory functions
Journal of Immunology, 2011Co-Authors: Nicole Joller, Nasim Kassam, Jason P Hafler, Boel Brynedal, Silvia Spoerl, Steven D Levin, Arlene H Sharpe, Vijay K KuchrooAbstract:Costimulatory molecules regulate the functional outcome of T cell activation, and disturbance of the balance between activating and inhibitory signals results in increased susceptibility to infection or the induction of autoimmunity. Similar to the well-characterized CD28/CTLA-4 costimulatory pathway, a newly emerging pathway consisting of CD226 and T cell Ig and ITIM domain (TIGIT) has been associated with susceptibility to multiple autoimmune diseases. In this study, we examined the role of the putative coinhibitory molecule TIGIT and show that loss of TIGIT in mice results in hyperproliferative T cell responses and increased susceptibility to autoimmunity. TIGIT is thought to indirectly inhibit T cell responses by the induction of tolerogenic dendritic cells. By generating an agonistic anti-TIGIT Ab, we demonstrate that TIGIT can inhibit T cell responses directly independent of APCs. Microarray analysis of T cells stimulated with agonistic anti-TIGIT Ab revealed that TIGIT can act directly on T cells by attenuating TCR-driven activation signals.
David A Hafler - One of the best experts on this subject based on the ideXlab platform.
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differential expression of the t cell inhibitor TIGIT in glioblastoma and ms
Neuroimmunology and Neuroinflammation, 2020Co-Authors: Liliana E Lucca, Danielle Debartolo, Calvin Park, Benjamin A Lerner, Gerald Ponath, Khadir Raddassi, Brian Harnett, Varun Kumar, Anita Huttner, David A HaflerAbstract:Objective To identify coinhibitory immune pathways important in the brain, we hypothesized that comparison of T cells in lesions from patients with MS with tumor-infiltrating T cells (TILs) from patients with glioblastoma multiforme may reveal novel targets for immunotherapy. Methods We collected fresh surgical resections and matched blood from patients with glioblastoma, blood and unmatched postmortem CNS tissue from patients with MS, and blood from healthy donors. The expression of TIGIT, CD226, and their shared ligand CD155 as well as PD-1 and PDL1 was assessed by both immunohistochemistry and flow cytometry. Results We found that TIGIT was highly expressed on glioblastoma-infiltrating T cells, but was near-absent from MS lesions. Conversely, lymphocytic expression of PD-1/PD-L1 was comparable between the 2 diseases. Moreover, TIGIT was significantly upregulated in circulating lymphocytes of patients with glioblastoma compared with healthy controls, suggesting recirculation of TILs. Expression of CD226 was also increased in glioblastoma, but this costimulatory receptor was expressed alongside TIGIT in the majority of tumor-infiltrating T cells, suggesting functional counteraction. Conclusions The opposite patterns of TIGIT expression in the CNS between MS and glioblastoma reflects the divergent features of the immune response in these 2 CNS diseases. These data raise the possibility that anti-TIGIT therapy may be beneficial for patients with glioblastoma.
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differential expression of the t cell inhibitor TIGIT in glioblastoma and multiple sclerosis
bioRxiv, 2019Co-Authors: Liliana E Lucca, David A Hafler, Danielle Debartolo, Calvin Park, Benjamin A Lerner, Gerald Ponath, Khadir Raddassi, David PittAbstract:Abstract To identify co-inhibitory immune pathways important in the brain, we hypothesized that comparison of T cells in lesions from patients with MS with tumor infiltrating T cells (TILs) from patients with GBM may reveal novel targets for immunotherapy. Focusing on PD-1 and TIGIT, we found that TIGIT and its ligand CD155 were highly expressed on GBM TILs but were near-absent in MS lesions, while lymphocytic expression of PD-1/PDL-1 was comparable. TIGIT was also upregulated in peripheral lymphocytes in GBM, suggesting recirculation of TILs. These data raise the possibility that anti-TIGIT therapy may be beneficial for patients with glioblastoma.
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TIGIT signaling restores suppressor function of th1 tregs
JCI insight, 2019Co-Authors: Liliana E Lucca, Pierrepaul Axisa, Emily Singer, Neal M Nolan, Margarita Dominguezvillar, David A HaflerAbstract:Th1 Tregs are characterized by the acquisition of proinflammatory cytokine secretion and reduced suppressor activity. Th1 Tregs are found at increased frequency in autoimmune diseases, including type 1 diabetes and multiple sclerosis (MS). We have previously reported that in vitro stimulation with IL-12 recapitulates the functional and molecular features of MS-associated Th1 Tregs, revealing a central role for hyperactivation of the Akt pathway in their induction. TIGIT is a newly identified coinhibitory receptor that marks Tregs that specifically control Th1 and Th17 responses. Here, we report that signaling through TIGIT counteracts the action of IL-12 in inducing the Th1 program. Specifically, TIGIT signaling represses production of IFN-γ and T-bet expression and restores suppressor function in Tregs treated with IL-12. FoxO1 functional inhibition abolishes the protective effect of TIGIT, indicating that TIGIT signaling promotes FoxO1 nuclear localization. Consistent with this observation, signaling through TIGIT leads to a rapid suppression of Akt function and FoxO1 phosphorylation. Finally, TIGIT stimulation reduces the production of IFN-γ and corrects the suppressor defect of Tregs from patients with MS. Our results indicate an important role for TIGIT in controlling the functional stability of Tregs through repression of Akt, suggesting that the TIGIT pathway could be targeted for immunomodulatory therapies in human autoimmune disorders.
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the TIGIT cd226 cd155 axis is differentially expressed in ms and glioblastoma implications for autoimmunity and tumor immune escape p4 043
Neurology, 2015Co-Authors: Daniel E Lowther, Xiangguo Duan, David A Hafler, Sriram Ramanan, Danielle Debartolo, Calvin Park, David PittAbstract:OBJECTIVE: To determine expression of the co-inhibitory T cell immunoreceptor with Ig and ITIM domains (TIGIT), the co-stimulatory receptor CD226 and their ligand CD155 in multiple sclerosis (MS) and glioblastoma multiforme (GBM). BACKGROUND: TIGIT is a newly identified receptor that inhibits T cell function by competing with the co-stimulatory receptor CD226 for the same ligand, CD155. TIGIT is one of several negative immune regulators that inhibit autoreactive T cells and suppress development of autoimmunity. Importantly, the TIGIT/CD226 pathway has been linked to MS susceptibility through genome-wide association studies. Activity of TIGIT/CD226 in the immune response to GBM has not been examined. MS and GBM represent opposites of the inflammatory spectrum with an unchecked autoimmune response in MS and failure of the immune system to clear tumor cells in GBM. DESIGN/METHODS: MS, GBM and control CNS autopsy tissue was labeled with antibodies against TIGIT, CD226 and CD155 and markers for lymphocytes and microglia/macrophages. Infiltrating immune cells isolated from fresh GBM tumor biopsies and matched peripheral blood were analyzed by flow cytometry. RESULTS: The co-inhibitory molecule TIGIT was expressed in mononuclear cell infiltrates in GBM but was near-absent from inflammatory cells in MS lesions. The co-stimulatory receptor CD226 was highly expressed by lymphocytes in both MS and GBM. Similarly, the ligand for TIGIT and CD226, CD155, was present in inflammatory infiltrates in MS and GBM. TIGIT expression was significantly upregulated by flow cytometry analysis on GBM infiltrating CD8+ and regulatory CD4+ T cells compared to the peripheral blood of matched GBM patients, MS patients and healthy controls. CONCLUSIONS: These data suggest that TIGIT engagement by CD155 may be a checkpoint inhibitor for tumor evasion in the CNS, while loss of TIGIT expression on infiltrating mononuclear cells in MS tissue leads to an autoimmune response. Manipulation of these pathways may have therapeutic potential. Disclosure: Dr. Lowther has received research support from Bristol-Myers Squibb. Dr. Ramanan has nothing to disclose. Dr. DeBartolo has nothing to disclose. Dr. Park has nothing to disclose. Dr. Duan has nothing to disclose. Dr. Hafler has received personal compensation for activities with Genzyme, NKT Therapeutics, and Novartis as a consultant. Dr. Pitt has received personal compensation for activities with Biogen Idec as a consultant and/or speaker.
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the TIGIT cd226 axis regulates human t cell function
Journal of Immunology, 2012Co-Authors: Ester Lozano, Vijay K Kuchroo, Margarita Dominguezvillar, David A HaflerAbstract:T cell Ig and ITIM domain (TIGIT) is a newly identified receptor expressed on T cells that binds to CD155 on the dendritic cell surface, driving them to a more tolerogenic phenotype. Given that TIGIT contains an ITIM motif in its intracellular domain and considering the potential importance of the TIGIT/CD226 pathway in human autoimmune disease, we investigated the specific role of TIGIT in human CD4 + T cells. Using an agonistic anti-TIGIT mAb, we demonstrate a direct inhibitory effect on T cell proliferation with a decrease in expression of T-bet, GATA3, IFN regulatory factor 4, and retinoic acid-related orphan receptor c with inhibition of cytokine production, predominantly IFN-γ. Knockdown of TIGIT expression by short hairpin RNA resulted in an increase of both T-bet and IFN-γ mRNA and protein expression with concomitant decrease in IL-10 expression. Increases in IFN-γ with TIGIT knockdown could be overcome by blocking CD226 signaling, indicating that TIGIT exerts immunosuppressive effects by competing with CD226 for the same CD155 ligand. These data demonstrate that TIGIT can inhibit T cell functions by competing with CD226 and can also directly inhibit T cells in a T cell-intrinsic manner. Our results provide evidence for a novel role of this alternative costimulatory pathway in regulating human T cell responses associated with autoimmune disease.
Vijay K Kuchroo - One of the best experts on this subject based on the ideXlab platform.
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tim 3 lag 3 and TIGIT
Current Topics in Microbiology and Immunology, 2017Co-Authors: Nicole Joller, Vijay K KuchrooAbstract:Co-inhibitory receptors play a key role in regulating T cell responses and maintaining immune homeostasis. Their inhibitory function prevents autoimmune responses but also restricts the ability of T cells to mount effective immune responses against tumors or persistent pathogens. T cells express a module of co-inhibitory receptors, which display great diversity in expression, structure, and function. Here, we focus on the co-inhibitory receptors Tim-3, Lag-3, and TIGIT and how they regulate T cell function, maintenance of self-tolerance, their role in regulating ongoing T cell responses at peripheral tissues, and their synergistic effects in regulating autoimmunity and antitumor responses.
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mechanisms of TIGIT driven immune suppression in cancer
Journal for ImmunoTherapy of Cancer, 2014Co-Authors: Sema Kurtulus, Nicole Joller, Vijay K Kuchroo, Kaori Sakuishi, Dewar J Tan, Mark J Smyth, Huiyuan Zhang, Ana C AndersonAbstract:Meeting abstracts TIGIT is a co-inhibitory molecule that limits T cell proliferation and activation. TIGIT expression has been recently shown to identify a subset of regulatory T cells (Treg) that specifically suppresses Th1 and Th17 responses; however its role in tumor immunity has not been
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the TIGIT cd226 axis regulates human t cell function
Journal of Immunology, 2012Co-Authors: Ester Lozano, Vijay K Kuchroo, Margarita Dominguezvillar, David A HaflerAbstract:T cell Ig and ITIM domain (TIGIT) is a newly identified receptor expressed on T cells that binds to CD155 on the dendritic cell surface, driving them to a more tolerogenic phenotype. Given that TIGIT contains an ITIM motif in its intracellular domain and considering the potential importance of the TIGIT/CD226 pathway in human autoimmune disease, we investigated the specific role of TIGIT in human CD4 + T cells. Using an agonistic anti-TIGIT mAb, we demonstrate a direct inhibitory effect on T cell proliferation with a decrease in expression of T-bet, GATA3, IFN regulatory factor 4, and retinoic acid-related orphan receptor c with inhibition of cytokine production, predominantly IFN-γ. Knockdown of TIGIT expression by short hairpin RNA resulted in an increase of both T-bet and IFN-γ mRNA and protein expression with concomitant decrease in IL-10 expression. Increases in IFN-γ with TIGIT knockdown could be overcome by blocking CD226 signaling, indicating that TIGIT exerts immunosuppressive effects by competing with CD226 for the same CD155 ligand. These data demonstrate that TIGIT can inhibit T cell functions by competing with CD226 and can also directly inhibit T cells in a T cell-intrinsic manner. Our results provide evidence for a novel role of this alternative costimulatory pathway in regulating human T cell responses associated with autoimmune disease.
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cutting edge TIGIT has t cell intrinsic inhibitory functions
Journal of Immunology, 2011Co-Authors: Nicole Joller, Nasim Kassam, Jason P Hafler, Boel Brynedal, Silvia Spoerl, Steven D Levin, Arlene H Sharpe, Vijay K KuchrooAbstract:Costimulatory molecules regulate the functional outcome of T cell activation, and disturbance of the balance between activating and inhibitory signals results in increased susceptibility to infection or the induction of autoimmunity. Similar to the well-characterized CD28/CTLA-4 costimulatory pathway, a newly emerging pathway consisting of CD226 and T cell Ig and ITIM domain (TIGIT) has been associated with susceptibility to multiple autoimmune diseases. In this study, we examined the role of the putative coinhibitory molecule TIGIT and show that loss of TIGIT in mice results in hyperproliferative T cell responses and increased susceptibility to autoimmunity. TIGIT is thought to indirectly inhibit T cell responses by the induction of tolerogenic dendritic cells. By generating an agonistic anti-TIGIT Ab, we demonstrate that TIGIT can inhibit T cell responses directly independent of APCs. Microarray analysis of T cells stimulated with agonistic anti-TIGIT Ab revealed that TIGIT can act directly on T cells by attenuating TCR-driven activation signals.
Dan L Eaton - One of the best experts on this subject based on the ideXlab platform.
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the immunoreceptor TIGIT regulates antitumor and antiviral cd8 t cell effector function
Cancer Cell, 2014Co-Authors: Robert J Johnston, Laetitia Compsagrar, Bryan Irving, Jason A Hackney, Mahrukh Huseni, Yagai Yang, Summer Park, Vincent Javinal, Henry Chiu, Dan L EatonAbstract:Tumors constitute highly suppressive microenvironments in which infiltrating T cells are "exhausted" by inhibitory receptors such as PD-1. Here we identify TIGIT as a coinhibitory receptor that critically limits antitumor and other CD8(+) T cell-dependent chronic immune responses. TIGIT is highly expressed on human and murine tumor-infiltrating T cells, and, in models of both cancer and chronic viral infection, antibody coblockade of TIGIT and PD-L1 synergistically and specifically enhanced CD8(+) T cell effector function, resulting in significant tumor and viral clearance, respectively. This effect was abrogated by blockade of TIGIT's complementary costimulatory receptor, CD226, whose dimerization is disrupted upon direct interaction with TIGIT in cis. These results define a key role for TIGIT in inhibiting chronic CD8(+) T cell-dependent responses.
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TIGIT inhibits cd8 t cell effector function during chronic viral infection and cancer tum7p 933
Journal of Immunology, 2014Co-Authors: Jane L Grogan, Laetitia Compsagrar, Dan L Eaton, Robert J Johnston, Jason A Hackney, Mahrukh Huseni, Yagai Yang, Summer ParkAbstract:Tumors constitute highly suppressive microenvironments in which infiltrating T cells are functionally suppressed by co-inhibitory receptor ligands. We identify T cell Immunoglobulin and ITIM domain (TIGIT) as a co-inhibitory receptor that critically limits CD8+ T cell responses to cancer and chronic infection. Expression of TIGIT was highly correlated with T cell infiltration in a broad range of solid tumors, and both human and murine tumor-infiltrating lymphocytes coordinately expressed TIGIT and PD-1, a key marker of T cell exhaustion. In mouse models of chronic viral infection and cancer, antibody blockades of TIGIT and PD-L1 synergistically and selectively enhanced CD8+ T cell effector function, resulting in significant viral clearance and tumor rejection respectively. Anti-TIGIT mediated anti-tumor immune responses were durable, as treated mice possessed antigen-specific and CD8+ T cell-dependent protection against tumor re-challenge. Strikingly, these effects were dependent on the activity of TIGIT’s complementary co-stimulatory receptor, CD226, whose dimerization and function was impaired by direct interaction with TIGIT in cis; and ablation of TIGIT was sufficient to enhance CD226 co-stimulation in CD8+ T cells. These results reveal a novel mechanism of action for co-inhibitory receptors and define a critical role for TIGIT as a regulator of anti-tumor and other chronic CD8+ T cell responses in vivo.
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structure of TIGIT immunoreceptor bound to poliovirus receptor reveals a cell cell adhesion and signaling mechanism that requires cis trans receptor clustering
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: K F Stengel, K Hardenbowles, Laurent Rouge, Laetitia Compsagrar, Dan L Eaton, Christian Wiesmann, Xin Yu, J. Fernando Bazan, Jane L GroganAbstract:Nectins (nectin1–4) and Necls [nectin-like (Necl1–5)] are Ig superfamily cell adhesion molecules that regulate cell differentiation and tissue morphogenesis. Adherens junction formation and subsequent cell–cell signaling is initiated by the assembly of higher-order receptor clusters of cognate molecules on juxtaposed cells. However, the structural and mechanistic details of signaling cluster formation remain unclear. Here, we report the crystal structure of poliovirus receptor (PVR)/Nectin-like-5/CD155) in complex with its cognate immunoreceptor ligand T-cell-Ig-and-ITIM-domain (TIGIT). The TIGIT/PVR interface reveals a conserved specific “lock-and-key” interaction. Notably, two TIGIT/PVR dimers assemble into a heterotetramer with a core TIGIT/TIGIT cis-homodimer, each TIGIT molecule binding one PVR molecule. Structure-guided mutations that disrupt the TIGIT/TIGIT interface limit both TIGIT/PVR-mediated cell adhesion and TIGIT-induced PVR phosphorylation in primary dendritic cells. Our data suggest a cis-trans receptor clustering mechanism for cell adhesion and signaling by the TIGIT/PVR complex and provide structural insights into how the PVR family of immunoregulators function.
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the surface protein TIGIT suppresses t cell activation by promoting the generation of mature immunoregulatory dendritic cells
Nature Immunology, 2009Co-Authors: Xin Yu, Kristin D. Harden, Lino C. Gonzalez, Michelle Francesco, Eugene Chiang, Bryan Irving, Sinisa Ivelja, Canio J. Refino, Hilary Clark, Dan L EatonAbstract:Dendritic cells (DCs) can promote or inhibit T cell responses. Grogan and colleagues show that the T cell protein TIGIT, by engaging poliovirus receptor on DCs, promotes DC interleukin 10 production, which inhibits T cell activation. Here we have identified a surface protein, TIGIT, containing an immunoglobulin variable domain, a transmembrane domain and an immunoreceptor tyrosine-based inhibitory motif that was expressed on regulatory, memory and activated T cells. Poliovirus receptor, which is expressed on dendritic cells, bound TIGIT with high affinity. A TIGIT-Fc fusion protein inhibited T cell activation in vitro, and this was dependent on the presence of dendritic cells. The binding of poliovirus receptor to TIGIT on human dendritic cells enhanced the production of interleukin 10 and diminished the production of interleukin 12p40. Knockdown of TIGIT with small interfering RNA in human memory T cells did not affect T cell responses. TIGIT-Fc inhibited delayed-type hypersensitivity reactions in wild-type but not interleukin 10–deficient mice. Our data suggest that TIGIT exerts immunosuppressive effects by binding to poliovirus receptor and modulating cytokine production by dendritic cells.
Mark J Smyth - One of the best experts on this subject based on the ideXlab platform.
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TIGIT and cd96 new checkpoint receptor targets for cancer immunotherapy
Immunological Reviews, 2017Co-Authors: William C Dougall, Sema Kurtulus, Mark J Smyth, Ana C AndersonAbstract:While therapies targeting the co-inhibitory or immune checkpoint receptors PD-1 and CTLA-4 have shown remarkable success in many cancers, not all patients benefit from these therapies. This has catalyzed enormous interest in the targeting of other immune checkpoint receptors. In this regard, TIGIT and CD96 have recently entered the limelight as novel immune checkpoint receptor targets. TIGIT and CD96 together with the co-stimulatory receptor CD226 form a pathway that is analogous to the CD28/CTLA-4 pathway, in which shared ligands and differential receptor:ligand affinities fine-tune the immune response. Although the roles of TIGIT and CD96 as immune checkpoint receptors in T cell and natural killer cell biology are just beginning to be uncovered, accumulating data support the targeting of these receptors for improving anti-tumor immune responses. A clear understanding of the immune cell populations regulated by TIGIT and CD96 is key to the design of immunotherapies that target these receptors in combination with other existing immune checkpoint blockade therapies.
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molecular pathways targeting cd96 and TIGIT for cancer immunotherapy
Clinical Cancer Research, 2016Co-Authors: Stephen J Blake, Michele W L Teng, Mark J Smyth, William C Dougall, John J MilesAbstract:The receptors CD96 and TIGIT are expressed on the surface of T and natural killer (NK) cells, and recent studies suggest both play important inhibitory roles in immune function. CD96 has been shown to modulate immune cell activity in mice, with Cd96-/- mice displaying hypersensitive NK-cell responses to immune challenge and significant tumor resistance. TIGIT overexpression has been shown to reduce NK-cell-mediated cytotoxicity. TIGIT is also upregulated on T cells during cancer and chronic viral infection, with expression associated with effector T-cell exhaustion and increased regulatory T-cell suppression. The counterbalance between the putative inhibitory CD96 and TIGIT receptors and the activating receptor, CD226, offers unique strategies for immuno-oncology drug development. Blocking CD96 or TIGIT with mAbs has been shown to improve tumor control in mice, in particular when used in combination with PD-1/PD-L1 blockade. These results have highlighted these pathways as promising new targets for immune modulation. This review will examine the rationale behind targeting CD96 and TIGIT, and discuss the potential approaches in translating these preclinical findings into novel clinical agents. Clin Cancer Res; 22(21); 5183-8. ©2016 AACR.
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TIGIT predominantly regulates the immune response via regulatory t cells
Journal of Clinical Investigation, 2015Co-Authors: Sema Kurtulus, Nicole Joller, Kaori Sakuishi, Shin Foong Ngiow, Dewar J Tan, Michele W L Teng, Mark J SmythAbstract:Coinhibitory receptors are critical for the maintenance of immune homeostasis. Upregulation of these receptors on effector T cells terminates T cell responses, while their expression on Tregs promotes their suppressor function. Understanding the function of coinhibitory receptors in effector T cells and Tregs is crucial, as therapies that target coinhibitory receptors are currently at the forefront of treatment strategies for cancer and other chronic diseases. T cell Ig and ITIM domain (TIGIT) is a recently identified coinhibitory receptor that is found on the surface of a variety of lymphoid cells, and its role in immune regulation is just beginning to be elucidated. We examined TIGIT-mediated immune regulation in different murine cancer models and determined that TIGIT marks the most dysfunctional subset of CD8+ T cells in tumor tissue as well as tumor-tissue Tregs with a highly active and suppressive phenotype. We demonstrated that TIGIT signaling in Tregs directs their phenotype and that TIGIT primarily suppresses antitumor immunity via Tregs and not CD8+ T cells. Moreover, TIGIT+ Tregs upregulated expression of the coinhibitory receptor TIM-3 in tumor tissue, and TIM-3 and TIGIT synergized to suppress antitumor immune responses. Our findings provide mechanistic insight into how TIGIT regulates immune responses in chronic disease settings.
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mechanisms of TIGIT driven immune suppression in cancer
Journal for ImmunoTherapy of Cancer, 2014Co-Authors: Sema Kurtulus, Nicole Joller, Vijay K Kuchroo, Kaori Sakuishi, Dewar J Tan, Mark J Smyth, Huiyuan Zhang, Ana C AndersonAbstract:Meeting abstracts TIGIT is a co-inhibitory molecule that limits T cell proliferation and activation. TIGIT expression has been recently shown to identify a subset of regulatory T cells (Treg) that specifically suppresses Th1 and Th17 responses; however its role in tumor immunity has not been
