CD226 opposes TIGIT to disrupt Tregs in melanoma

Fourcade, Julien; Sun, Zhaojun; Chauvin, Joë-Marc; Ka, Mignane; Davar, Diwakar; Pagliano, Ornella; Wang, Hong; Saada, Sofiane; Menna, Carmine; Amin, Rada; Sander, Cindy; Kirkwood, John M.; Korman, Alan J.; Zarour, Hassane M.

doi:10.1172/jci.insight.121157

Cited by 146 publications

(141 citation statements)

References 45 publications

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“…However, recent studies have revealed previously unappreciated intrinsic roles of TIGIT in Treg cells. Despite previous observations that TIGIT expression marks a highly suppressive population of Treg cells, the exact underlying mechanisms and the potential roles of intrinsic TIGIT‐signaling in Treg cells have not been fully elucidated. Whereas effector T cells up‐regulate both CD226 and TIGIT upon activation, Treg cells preferentially up‐regulate TIGIT over CD226 .…”

Section: Inhibitory Receptorsmentioning

confidence: 97%

“…Despite previous observations that TIGIT expression marks a highly suppressive population of Treg cells, the exact underlying mechanisms and the potential roles of intrinsic TIGIT‐signaling in Treg cells have not been fully elucidated. Whereas effector T cells up‐regulate both CD226 and TIGIT upon activation, Treg cells preferentially up‐regulate TIGIT over CD226 . CD226‐signaling detrimentally impacts Treg cell stability and function, and TIGIT–PVR interaction was required to maintain the suppressive function of Treg cells .…”

Section: Inhibitory Receptorsmentioning

confidence: 97%

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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: Inhibitory Receptorsmentioning

confidence: 97%

Section: Inhibitory Receptorsmentioning

confidence: 97%

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

et al. 2019

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“…Moreover, TIGIT competes for its ligands CD112 and CD155 with the costimulatory receptor CD226 which, unlike conventional T cells, is associated with functionally suppressed Treg cells. 132 This study suggests that the CD226/TIGIT ratio correlates with Treg cell stability, and clinical outcome in individuals with melanoma. Moreover, both CD112 and CD155 over-expression is reported in cancer, 133 although further work is required to delineate the interaction dynamics with the multiple TIGIT-expressing cell-types.…”

Section: Co-inhibitory Receptorsmentioning

confidence: 69%

“…Interestingly, TIGIT + Treg cells preferentially suppress Th1 and Th17 (but not Th2) cells, the former being important in anti‐tumour immunity. Moreover, TIGIT competes for its ligands CD112 and CD155 with the co‐stimulatory receptor CD226 which, unlike conventional T cells, is associated with functionally suppressed Treg cells . This study suggests that the CD226/TIGIT ratio correlates with Treg cell stability, and clinical outcome in individuals with melanoma.…”

Section: Regulation Of Treg Cells In Cancermentioning

confidence: 77%

Regulation of regulatory T cells in cancer

2019

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Summary The inflammatory response to transformed cells forms the cornerstone of natural or therapeutically induced protective immunity to cancer. Regulatory T (Treg) cells are known for their critical role in suppressing inflammation, and therefore can antagonize effective anti‐cancer immune responses. As such, Treg cells can play detrimental roles in tumour progression and in the response to both conventional and immune‐based cancer therapies. Recent advances in our understanding of Treg cells reveal complex niche‐specific regulatory programmes and functions, which are likely to extrapolate to cancer. The regulation of Treg cells is reliant on upstream cues from haematopoietic and non‐immune cells, which dictates their genetic, epigenetic and downstream functional programmes. In this review we will discuss how Treg cells are themselves regulated in normal and transformed tissues, and the implications of this cross talk on tumour growth.

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“…Elucidating the factors influencing Treg function is important for understanding the disease pathogenesis and further identifying therapeutic opportunities. In recent studies, Tregs were observed to exhibit increased TIGIT expression and decreased CD226 expression compared to CD4 + effector T cells, resulting in an increased TIGIT/CD226 ratio in the periphery and at the tumor sites of melanoma patients . Thus, CD226 and TIGIT exert opposing effects in Tregs upon CD155 binding .…”

Section: Introductionmentioning

confidence: 99%

CD226 deficiency on regulatory T cells aggravates renal fibrosis via up-regulation of Th2 cytokines through miR-340

Zhang

Liu

et al. 2019

Journal of Leukocyte Biology

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In this study, we observed that deletion of CD226 on regulatory T cells (Tregs) precedes renal fibrosis in a mouse unilateral ureteral obstruction (UUO) model. First, we generated Treg‐specific CD226 gene knockout mice (CD226fl/fl Foxp3YFP‐Cre). Next, CD226fl/fl Foxp3YFP‐Cre mice and Foxp3YFP‐Cre control mice were subjected to UUO surgery. Pathologic analysis and Sirius red and Masson's trichrome staining showed that the kidneys of CD226fl/fl Foxp3YFP‐Cre mice following UUO showed much more severe interstitial fibrosis than Foxp3YFP‐Cre control mice at days 10 and 20. Additionally, CD226fl/fl Foxp3YFP‐Cre mice showed increased fibronectin expression, as demonstrated by immunohistochemistry (IHC) staining. Although Treg cell‐restricted CD226 deficiency showed increased Foxp3+ expression, expression of the cell surface functional molecule CD103 was significantly reduced, indicating impaired homeostasis in the Tregs of CD226fl/fl Foxp3YFP‐Cre mice. To better understand CD226 function, RNA sequencing (RNA‐Seq) analysis was conducted in Tregs isolated from CD226fl/fl Foxp3YFP‐Cre and Foxp3YFP‐Cre mice. RNA‐Seq data showed that the helper T cell (Th) 2‐related cytokines IL‐4 and IL‐10 were significantly up‐regulated in CD226 deficient Tregs. In addition, mRNA analysis of kidney samples from the mice following UUO by qPCR also showed increased IL‐4 and IL‐10 expression in CD226fl/fl Foxp3YFP‐Cre mice, as well as elevated TGF‐β1 levels, indicating that CD226 deficiency in Tregs resulted in the acquisition of the ability to produce Th2 cytokines. Finally, we found that microRNA‐340 (miR‐340), which was down‐regulated in Tregs isolated from CD226fl/fl Foxp3YFP‐Cre mice, directly regulated IL‐4 gene expression in vitro. These data suggest that the promotion of CD226 signaling on Tregs is a therapeutic target for renal disease.

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CD226 opposes TIGIT to disrupt Tregs in melanoma

Cited by 146 publications

References 45 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

Regulation of regulatory T cells in cancer

CD226 deficiency on regulatory T cells aggravates renal fibrosis via up-regulation of Th2 cytokines through miR-340

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