TIGIT signaling restores suppressor function of Th1 Tregs

Lucca, Liliana E.; Axisa, Pierre-Paul; Singer, Emily; Nolan, Neal M.; Dominguez‐Villar, Margarita; Hafler, David A.

doi:10.1172/jci.insight.124427

Cited by 87 publications

(64 citation statements)

References 47 publications

(70 reference statements)

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“…56 Furthermore, a recent study has demonstrated that TIGIT-signaling repressed the PI3K-Akt axis in an inositol polyphosphate-5-phosphatase Ddependent manner leading to sustained nuclear localization of Foxo1, which was required to rescue Treg cells from an IFN-c-secreting effector Th1-like Treg phenotype induced by IL-12 in a highly inflammatory environment, such as multiple sclerosis. 57 These observations suggest that unlike LAG3, TIGIT is a selective IR that represses effector T-cell function while enhancing Treg cell stability and function. Consistently, increased infiltration of TIGIT + Treg cells has been correlated with poor prognosis of patients with melanoma.…”

Section: T-cell Immunoreceptor With Immunoglobulin and Itim Domainsmentioning

confidence: 99%

“…CD226‐signaling detrimentally impacts Treg cell stability and function, and TIGIT–PVR interaction was required to maintain the suppressive function of Treg cells . Furthermore, a recent study has demonstrated that TIGIT‐signaling repressed the PI3K‐Akt axis in an inositol polyphosphate‐5‐phosphatase D‐dependent manner leading to sustained nuclear localization of Foxo1, which was required to rescue Treg cells from an IFN‐ γ ‐secreting effector Th1‐like Treg phenotype induced by IL‐12 in a highly inflammatory environment, such as multiple sclerosis . These observations suggest that unlike LAG3, TIGIT is a selective IR that represses effector T‐cell function while enhancing Treg cell stability and function.…”

Section: Inhibitory Receptorsmentioning

confidence: 99%

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Intratumoral regulatory T cells: markers, subsets and their impact on anti‐tumor immunity

et al. 2019

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Summary Regulatory T (Treg) cells play a crucial role in maintaining self‐tolerance and resolution of immune responses by employing multifaceted immunoregulatory mechanisms. However, Treg cells readily infiltrate into the tumor microenvironment (TME) and dampen anti‐tumor immune responses, thereby becoming a barrier to effective cancer immunotherapy. There has been a substantial expansion in the development of novel immunotherapies targeting various inhibitory receptors (IRs), such as CTLA4, PD1 and LAG3, but these approaches have mechanistically focused on the elicitation of anti‐tumor responses. However, enhanced inflammation in the TME could also play a detrimental role by facilitating the recruitment, stability and function of Treg cells by up‐regulating chemokines that promote Treg cell migration, and/or increasing inhibitory cytokine production. Furthermore, IR blockade may enhance Treg cell function and survival, thereby serving as a resistance mechanism against effective immunotherapy. Given that Treg cells are comprised of functionally and phenotypically heterogeneous sub‐populations that may alter their characteristics in a context‐dependent manner, it is critical to identify unique molecular pathways that are preferentially used by intratumoral Treg cells. In this review, we discuss markers that serve to identify certain Treg cell subsets, distinguished by chemokine receptors, IRs and cytokines that facilitate their migration, stability and function in the TME. We also discuss how these Treg cell subsets correlate with the clinical outcome of patients with various types of cancer and how they may serve as potential TME‐specific targets for novel cancer immunotherapies.

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Section: T-cell Immunoreceptor With Immunoglobulin and Itim Domainsmentioning

confidence: 99%

Section: Inhibitory Receptorsmentioning

confidence: 99%

Intratumoral regulatory T cells: markers, subsets and their impact on anti‐tumor immunity

et al. 2019

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“…15 Moreover, TIGIT is a marker of highly suppressive regulatory T cells (Tregs) and directly promotes Treg function in environments of Th1 inflammation. 16,17 TIGIT has been investigated as a novel candidate target of cancer immunotherapy. Indeed, increased TIGIT has been demonstrated on tumor-infiltrating lymphocytes in a number of cancers including non-small-cell lung cancer and melanoma.…”

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confidence: 99%

Differential expression of the T-cell inhibitor TIGIT in glioblastoma and MS

Lucca

Lerner

Park

et al. 2020

Neurol Neuroimmunol Neuroinflamm

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ObjectiveTo 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.MethodsWe 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.ResultsWe 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.ConclusionsThe 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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“…The involvement of TIGIT engagement in the suppression of PI3k/Akt/mTOR signaling suggests impaired metabolic activity of tumorinfiltrating NK cells. Moreover, we know that upstream inhibition of PI3K by TIGIT results in inhibition of mTOR [67]. In Tregs, production of TIGITcontrolled fibrinogen-like protein 2 (Fgl-2) was reported as driving the acquisition of tolerance to allografts following treatment of mice with the mTOR inhibitor rapamycin [68], thus suggesting a link between TIGIT and immune metabolic signaling.…”

Section: Tigitmentioning

confidence: 99%

Immunometabolic Responses of Natural Killer Cells to Inhibitory Tumor Microenvironment Checkpoints

Dao

Matosevic

2019

Immunometabolism

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NK cell trafficking and migration into solid tumors is often poor. Altered NK cell metabolism in the tumor microenvironment has been correlated with tumor invasiveness, metastasis and cellular dysfunction. Tumorinduced stresses correlate to limited numbers of functional NK cells in solid tumors and, consequently, limited survival. Metabolic impairment of NK cells in cancer is still not fully understood, but the involvement of inhibitory checkpoints-both tumor-associated as well as NK-specificplays a significant role in driving these responses. The metabolic reprogramming events that NK cells undergo in the tumor microenvironment are linked to their ability to support energy metabolism in scenarios of impaired glycolytic fueling and low oxygen. The contributions of inhibitory checkpoints to these events are not entirely known, but are emerging as increasingly significant to the restoration of NK cell function. Here, we discuss our understanding of the role of inhibitory receptors and checkpoints in the metabolic dysfunction of NK cells in solid tumors, as a critical key to the development of new immunotherapies.

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TIGIT signaling restores suppressor function of Th1 Tregs

Cited by 87 publications

References 47 publications

Intratumoral regulatory T cells: markers, subsets and their impact on anti‐tumor immunity

Intratumoral regulatory T cells: markers, subsets and their impact on anti‐tumor immunity

Differential expression of the T-cell inhibitor TIGIT in glioblastoma and MS

Immunometabolic Responses of Natural Killer Cells to Inhibitory Tumor Microenvironment Checkpoints

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