Cutting Edge: Th17 and Regulatory T Cell Dynamics and the Regulation by IL-2 in the Tumor Microenvironment

Kryczek, Ilona; Wei, Shuang; Zou, Linhua; Altuwaijri, Saleh; Szeliga, Wojciech; Kolls, Jay K.; Chang, Alfred E.; Zou, Weiping

doi:10.4049/jimmunol.178.11.6730

Cited by 371 publications

(375 citation statements)

References 30 publications

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“…In Although prior studies have reported that CD4 1 or CD8 1 T cells were implicated in IL-17 production in tumor-bearing hosts [3,34,35], these reports have not examined gd T cells. In our experiments, we showed that whereas small numbers of CD4 1 T cells produced IL-17, there were much more IL-17-producing gd T cells in the transplanted tumor tissues ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…It has been demonstrated that IL-17 is expressed in tumor microenvironments [3][4][5]. The precise role of IL-17 during tumor development, however, remains unclear.…”

Section: Il-17 Promotes Tumor Development By Enhancing Angiogenesismentioning

confidence: 99%

“…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].…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

“…It has been demonstrated that IL-17 is expressed in tumor microenvironments [3][4][5]. The precise role of IL-17 during tumor development, however, remains unclear.…”

Section: Il-17 Promotes Tumor Development By Enhancing Angiogenesismentioning

confidence: 99%

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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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“…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%

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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“…In the presence of TGF-␤1 and IL-6 and absence of IL-2, substantially greater numbers of IL-17-producing cells are generated, as previously reported. 27,35 The addition of ATRA inhibited IL-17 expression in the absence of IL-2 while enhancing FoxP3 expression ( Figure 7A, lower right panel). We confirmed these results using IL-2-deficient Rag2 Ϫ/Ϫ TCRtransgenic (5C.C7) naive T cells ( Figure S1, available on the Blood website; see the Supplemental Materials link at the top of the online article).…”

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confidence: 99%

Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway

Elias

Laurence

Davidson

et al. 2008

Blood

399

333

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IntroductionImmune responses are orchestrated by subsets of CD4 ϩ helper and effector T cells. Classically, differentiated T cells have been classified as belonging either to T-helper 1 (Th1) or Th2 lineages. 1 Th1 cells secrete interferon-gamma (IFN-␥) in response to interleukin-12 (IL-12) and require the transcription factors T-box21 (T-bet) and signal transducer and activator of transcription 4 (Stat4) 2 and Stat1, whereas Th2 cells secrete IL-4, IL-5, and IL-13 and require the transcription factors GATA-binding protein 3 (GATA-3) and Stat6. 3 While this simple paradigm was instrumental in understanding immune responses to model pathogens, it was less clear how such a model explained the pathogenesis of autoimmune disease.More recently, additional fates for CD4 ϩ T cells have emerged that provide more insights into the mechanisms of tolerance and immune-mediated disease. One of these new subsets of T cells, expressing the transcription factor FoxP3, is termed regulatory T cells (Tregs) and serves to inhibit immune responses. Deficiency of FoxP3 in mice and humans is associated with fatal autoimmune disease. 4,5 FoxP3 ϩ Tregs normally develop in the thymus, but FoxP3 expression and Treg function also develop when naive CD4 ϩ T cells are stimulated in vitro with transforming growth factor-␤1 (TGF-␤1) and IL-2. 6 Development and differentiation of Tregs and expression of FoxP3 are dependent upon another transcription factor, Stat5. 7,8 Another new subset of T cells that may be related to Tregs is a subset that produces the proinflammatory cytokine IL-17 (Th17 cells). Overproduction of IL-17 has been noted in a variety of models of autoimmune disease, including experimental autoimmune encephalomyelitis and collagen-induced arthritis. 9-13 Importantly, increased levels of IL-17 are also seen in human diseases, such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. 14-16 Th17 cells are generated by the cytokines TGF-␤1 and IL-6, the latter of which acts via Stat3 to induce the transcription factor retinoic acid orphan receptor gamma (ROR␥t). 17 Overexpression of ROR␥t induces IL-17 production, whereas deficiency of this transcription factor virtually abrogates Th17 differentiation.ROR␥t belongs to a superfamily of retinoid nuclear receptors that include the retinoic acid receptors (RARs), retinoid X receptors (RXRs), and other RORs. 18 A connection between retinoids and CD4 ϩ T-cell differentiation has long been recognized. Memory T cells from vitamin A-deficient mice have been found to overproduce . 19 In contrast, administration of the active metabolite of vitamin A, retinoic acid (RA), has been reported to suppress memory cell IFN-␥ production and increase IL-4 secretion. 20 Later, it emerged that vitamin A can be metabolized into retinoic acid isomers with different ligand-receptor affinities: 9-cis retinoic acid, with a higher affinity for the RXR family, and all-trans retinoic acid (ATRA), with a higher affinity for the RAR family. 21 Acting through RXR␣, 9-cis retinoic acid skews n...

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Cutting Edge: Th17 and Regulatory T Cell Dynamics and the Regulation by IL-2 in the Tumor Microenvironment

Cited by 371 publications

References 30 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

Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway

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