Regulation of Cutaneous Malignancy by γδ T Cells

Girardi, Michael; Oppenheim, David; Steele, Carrie R.; Lewis, Julia M.; Glusac, Earl J.; Filler, Renata; Hobby, P; Sutton, Brian J.; Tigelaar, Robert E.; Hayday, Adrian

doi:10.1126/science.1063916

Cited by 896 publications

(802 citation statements)

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“…However, within the tumor microenvironment, the balance between IL-12 and IL-23, which directly reflects Th1 and Th17 cell responses, is shifted toward IL-23 via activation of STAT3 [21,22]. Much attention has been paid to the finding that tumor stromal cells and tumor-associated macrophages, in part by producing IL-23, mainly contribute to the induction of cancer by promoting inflammation, whereas T cells suppress tumor development as part of the immunosurveillance system [23][24][25][26][27][28][29]. Recent research has provided evidence for the involvement of T cells in promoting tumor progression [28][29][30][31][32][33][34][35]; however, the precise effects of T cells and the cytokines they produce on tumorigenesis remain controversial.…”

Section: Introductionmentioning

confidence: 99%

“…This observation suggests that, in the case of B16 melanoma cells, IL-17 appears not to be involved in the promoting tumor growth. Resolving the mechanisms underlying these discrepancies would shed light on the regulation of anti-tumor immunity.It has been demonstrated that T cells, including abTCR 1 CD4 1 , abTCR 1 CD8 1 , and gdTCR 1 T cells, play a pivotal role in tumor immunosurveillance to eliminate tumor cells [23][24][25][26][27][28][29]. Recently, it has been shown that abTCR 1 CD4 1 and abTCR 1 CD8 1 T cells also act as tumor-promoting cells in various mouse Eur.…”

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Tumor‐infiltrating IL‐17‐producing γδ T cells support the progression of tumor by promoting angiogenesis

et al. 2010

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Based on the evidence that IL-17 is a key cytokine involved in various inflammatory diseases, we explored the critical role of IL-17-producing cd T cells for tumor development in tumor-bearing mouse model. IL-17 À/À mice exhibited a significant reduction of tumor growth, concomitantly with the decrease of vascular density at lesion area, indicating a pro-tumor property of IL-17. Among tumor-infiltrating lymphocytes (TIL), cd T cells were the major cellular source of IL-17. Analysis of TCR repertoires in TIL-cd T cells showed that circulating cd T cells, but not skin resident Vc5 1 cd T cells, produced IL-17. Neutralizing antibodies against IL-23, IL-6, and TGF-b, which were produced within the tumor microenvironment, inhibited the induction of IL-17-producing cd T cells. IL-17 production by tumor-infiltrating cd T cells was blocked by anti-cdTCR or anti-NKG2D antibodies, indicating that these ligands, expressed within the tumor microenvironment, are involved in cd T-cell activation. The IL-17-producing TIL-cd T cells exhibited reduced levels of perforin mRNA expression, but increased levels of COX-2 mRNA expression. Together, our findings support the novel concept that IL-17-producing cd T cells, generated in response to tumor microenvironment, act as tumor-promoting cells by inducing angiogenesis. IntroductionIn order to understand how tumor cells can escape immune surveillance mechanisms and thus develop anti-tumor therapies, it is critically important to investigate the mechanisms by which the immune system interacts with the tumor microenvironment. The tumor microenvironment, which is mainly composed of tumor cells, stromal cells, and tumor-infiltrating immune cells, is entirely different from noncancerous tissues. This unique microenvironment potently inhibits immune responses against tumor cells via various soluble mediators and contact-dependent mechanisms [1,2]. Previously, it was suggested that T-cell Eur. J. Immunol. 2010. 40: 1927-1937 DOI 10.1002 Cellular immune response 1927 responses within the local tumor tissue are completely inhibited. However, this concept was abandoned following the discovery of the regulatory T-cell and Th17 cell subsets, which are activated rather than suppressed in the tumor microenvironment via TGF-b and/or IL-6. Thus, the tumor microenvironment is conducive to IL-17 production. In fact, it has been shown that IL-17 is produced in human and murine tumor tissues [3][4][5]. Tumor cells promote neo-vascularization into tumor tissues through hyperproduction of angiogenic factors, which also support their own abnormal proliferation and survival [6]. It has been reported that tumor cells over-expressing IL-17 significantly promote new vessel growth into the tumor tissues [5]; however, physiological effects of IL-17 on tumor progression remain to be defined. Th17 differentiation from naïve CD4 1 T cells is regulated by TGF-b and IL-6. Proliferation, maintenance and full maturation of these cells are controlled by . Recently, it has been shown that IL-17 is produced by diverse T...

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

Tumor‐infiltrating IL‐17‐producing γδ T cells support the progression of tumor by promoting angiogenesis

et al. 2010

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“…Most of circulating  T lymphocytes from humans and primates express the HLA-unrestricted TCR V9V2 which is specific for small non-peptide phosphorylated metabolites (so-called phosphoantigens, PAg) which are frequently up regulated in human tumor cells [4]. NK and  T cells highly express NKG2D (a lectin-like type II transmembrane homodimer), a receptor allowing them to respond to ligands (MICA, MICB and ULBP 1-4) upregulated during oncogenic transformation and stress [5][6][7]. CD16 (a FcRIII receptor) expressed by NK and  T cells plays an important role in Antibody Dependant Cell Cytotoxicity (ADCC) which is of particular clinical interest with the increasing number of anti-cancer therapies using monoclonal antibodies [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

“…From its part, NKG2D has received considerable attention owing to evidence of its important role in immunosurveillance of tumors [6,7]. Indeed, genotoxic stress that activates DNA damage responses has been shown to induce the expression of NKG2D ligands (MICA, MICB, and ULBPs) and most of established tumor cell lines constitutively express one or more of these NKG2D ligands [43].…”

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“…NK and  T cells express high levels of NKG2D which has been shown to directly promote their cytotoxic responses against target cells [5,44]. Therefore, the recognition of NKG2D ligands on tumor cells must play an important role in tumor immunosurveillance or eradication by NK and  T cells [6,7,45]. Several inhibitory factors produced by tumor stroma such as TGF- have already been shown to interfere with the activation of NK cells by NKG2D triggering [46].…”

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PGE2 inhibits natural killer and γδ T cell cytotoxicity triggered by NKR and TCR through a cAMP-mediated PKA type I-dependent signaling

Martinet¹,

Jean²,

Dietrich³

et al. 2010

Biochemical Pharmacology

111

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inhibits Natural Killer and γδ T cell cytotoxicity triggered by NKR and TCR through a cAMPmediated PKA type I-dependent signaling. Biochemical Pharmacology, Elsevier, 2010, 80 (6) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Immunologic Study of Tumors in Mouse Models

Merghoub

Houghton

2004

Mouse Models of Human Cancer

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Mouse tumor models have played a central role in the history of cancer immunology and more broadly in immunology. Studies of transplantable tumors opened the field of transplantation immunology. Serologic analyses of antibodies against tumors led to the discovery of major histocompatibility complex (MHC) antigens that determine transplantation immunity as well as other alloantigens and lymphocyte subset markers, including the well‐known CD4+ and CD8+ subsets of T cells. In the present era, genetically manipulated mice are crucial tools to (1) understand the role of various components and cells of the immune system in promoting, accelerating, or rejecting tumors; (2) investigate immunity against cancers at different stages of tumor progression; and (3) develop and test new prevention and therapeutic strategies against cancer.

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Regulation of Cutaneous Malignancy by γδ T Cells

Cited by 896 publications

References 23 publications

Tumor‐infiltrating IL‐17‐producing γδ T cells support the progression of tumor by promoting angiogenesis

Tumor‐infiltrating IL‐17‐producing γδ T cells support the progression of tumor by promoting angiogenesis

PGE2 inhibits natural killer and γδ T cell cytotoxicity triggered by NKR and TCR through a cAMP-mediated PKA type I-dependent signaling

Immunologic Study of Tumors in Mouse Models

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