Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments

Kryczek, Ilona; Banerjee, Mousumi; Cheng, Pui; Vatan, Linhua; Szeliga, Wojciech; Wei, Shuang; Huang, Emina; Finlayson, Emily; Simeone, Diane M.; Welling, Theodore H.; Chang, Alfred E.; Coukos, George; Liu, Rebecca; Zou, Weiping

doi:10.1182/blood-2009-03-208249

Cited by 690 publications

(761 citation statements)

References 53 publications

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“…As we confirmed that human gd T cells differentiated into IL-17-producing cells, at least in the presence of IL-6, TGF-b and IL-23 (data not shown), IL-17 might be produced by gd T cells in these types of cancer. However, recent studies have shown that CD4 1 T cells were the main cellular source of IL-17 in human ovarian cancer tissues [40,41]. Therefore, in human cases, it is possible that the IL-17-producing cell subsets may vary among organs depending on the type of cancer.…”

Section: Discussionmentioning

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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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: Discussionmentioning

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 studies in both mouse and humans have focused upon CD8+ cytotoxic T cells that kill tumors directly and T H 1 CD4+ T cells (producing IL-2, and IFN-γ) that contribute directly or indirectly to tumor killing [43]. While T H 1 remains the dominant T H subset in tumors within the memory T cell pool, another T cell subset has recently been found in both mouse and human tumors that may play a significant role in the pathogenesis of tumors [44][45][46]. This subset is a CD4+ T cell that secretes IL-17A and has been labeled as the T H 17 cell [47,48].…”

Section: Inflammatory Leukocytes In the Tumor Microenvironmentmentioning

confidence: 99%

“…Their biological role in the tumor microenvironment is poorly understood, and at present suggested to be both beneficial and detrimental to the cancer patient [51]. The generation and regulation of T H 17 cells in ovarian cancer have been documented [45] and the possible function and clinical relevance of these cells in human tumor microenvironments reported [46]. It has been postulated that T H 17 cells contribute to protective human tumor immunity by inducing the production by tumor cells of two chemokines that attract and recruit effector T cells and effector memory T cells that express CXCR3, the receptor for the T H 17 induced chemokines CXCL9 (MIG) and CXCL10 (IP10) [46].…”

Section: Inflammatory Leukocytes In the Tumor Microenvironmentmentioning

confidence: 99%

“…The generation and regulation of T H 17 cells in ovarian cancer have been documented [45] and the possible function and clinical relevance of these cells in human tumor microenvironments reported [46]. It has been postulated that T H 17 cells contribute to protective human tumor immunity by inducing the production by tumor cells of two chemokines that attract and recruit effector T cells and effector memory T cells that express CXCR3, the receptor for the T H 17 induced chemokines CXCL9 (MIG) and CXCL10 (IP10) [46]. This could help to explain the dominance and sustained presence of the effector memory T cells in the microenvironment of human lung and ovarian tumors.…”

Section: Inflammatory Leukocytes In the Tumor Microenvironmentmentioning

confidence: 99%

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T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

Barnas

Simpson-Abelson

Yokota

et al. 2010

Cancer Microenvironment

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The immune system of cancer patients recognizes tumor-associated antigens expressed on solid tumors and these antigens are able to induce tumor-specific humoral and cellular immune responses. Diverse immunotherapeutic strategies have been used in an attempt to enhance both antibody and T cell responses to tumors. While several tumor vaccination strategies significantly increase the number of tumor-specific lymphocytes in the blood of cancer patients, most vaccinated patients ultimately experience tumor progression. CD4+ and CD8+ T cells with an effector memory phenotype infiltrate human tumor microenvironments, but most are hyporesponsive to stimulation via the T cell receptor (TCR) and CD28 under conditions that activate memory T cells derived from the peripheral blood of the cancer patients or normal donors. Attempts to identify cells and molecules responsible for the TCR signaling arrest of tumor-infiltrating T cells have focused largely upon the immunosuppressive effects of tumor cells, tolerogenic dendritic cells and regulatory T cells. Here we review potential mechanisms by which human T cell function is arrested in the tumor microenvironment with a focus on the immunomodulatory effects of stromal fibroblasts. Determining in vivo which cells and molecules are responsible for the TCR arrest in human tumor-infiltrating T cells will be necessary to formulate and test strategies to prevent or reverse the signaling arrest of the human T cells in situ for a more effective design of tumor vaccines. These questions are now addressable using novel human xenograft models of tumor microenvironments.

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“…The role of Th17 cells in cancer is still unclear. The inflammatory Th17 response correlates with poor disease outcome in prostate, head and neck and colorectal cancer [28,29]. However, IL-17 knockout mice exhibited increased susceptibility to metastasis of colon cancer MC38 cells, demonstrating an possible anti-tumor function of Th17 cells [30,31].…”

Section: Introductionmentioning

confidence: 99%

Tumor-Released Survivin Induces a Type-2 T Cell Response and Decreases Cytotoxic T Cell Function, in Vitro

Jutzy

Khan

Asuncion-Valenzuela

et al. 2012

Cancer Microenvironment

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Clinical studies of T cell profiles from cancer patients have shown a skewing toward a type-2 T cell response with decreased cytotoxic T cell function. However, the primary cause of this shift remains unknown. Here we show that tumor-released Survivin, an inhibitor of apoptosis (IAP) protein and tumor-specific antigen, is taken up by T cells and alters their response. The addition of Survivin to T cell cultures resulted in decreased T cell proliferation and reduced cytotoxic CD8 + T cell function. Additionally, type 1 cell numbers and IFN-γ and IL-2 production were significantly reduced, while IL-4 release and type 2 T cell numbers increased. In contrast, the function and numbers of Th17 and T regulatory cells were not affected. These studies show that tumor-released Survivin modulates T cells resulting in a phenotype similar to that observed in cancer patients with a polarity shift from a type 1 to a type 2 response.

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Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments

Cited by 690 publications

References 53 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

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

Tumor-Released Survivin Induces a Type-2 T Cell Response and Decreases Cytotoxic T Cell Function, in Vitro

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