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

Abstract

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...

Murine CD27 (−) Vγ6 (+) γδ T cells producing IL-17A promote ovarian cancer growth via mobilization of protumor small peritoneal macrophages

“…Similarly, a recent report on colorectal cancer showed a positive correlation between clinopathological parameters and the infiltration of γδ T cells specifically producing interleukin-17 (IL-17) (17). A tumor-promoting function of γδ T cells was also suggested in murine fibrosarcoma (18) and hepatocellular carcinoma (19) models, in which γδ T cells were the major cellular source of IL-17, which was required for optimal tumor growth in vivo. These data raise the interesting question as to whether distinct functional attributes of γδ T cells, for example differential cytokine production, may associate with markedly different outcomes for tumor growth.…”

“…However, these experiments were performed on the murine BALB/c background, where lymphoid organs (both in naïve and tumor-bearing mice) were essentially depleted of IFN-γ-producing γδ T cells (18). By contrast, our study was conducted on the murine C57/Bl6 background, where IFN-γ-producing γδ T cells significantly outnumber their IL-17 (+) counterparts (20).…”

“…In a previous study on a fibrosarcoma (and colon carcinoma) model(s), γδ T cells were shown to be the major cellular source of IL-17, which supported tumor cell growth (18). However, these experiments were performed on the murine BALB/c background, where lymphoid organs (both in naïve and tumor-bearing mice) were essentially depleted of IFN-γ-producing γδ T cells (18).…”

“…Moreover, unlike the previous report (18), our study used TCRδ-deficient mice as a critical tool to establish the tumor-promoting role of γδ T cells in vivo. This raises interesting questions regarding γδ T-cell functions in the ID8 ovarian tumor environment in comparison with other models where an overt antitumor role has been demonstrated for γδ T cells (4)(5)(6)(7)45).…”

Nitric oxide synthase 2 is involved in the pro-tumorigenic potential of γδ17 T cells in melanoma

“…19 Moreover, Wakita et al indicated that gd17 cells promote angiogenesis via induction of VEGF secretion. 25 As gd17 cells may exert antitumor functions, [5][6][7]26 we decided to directly investigate the role of gd T cells in our model. Their pro-tumor properties were evidenced by the significant delay in metastasis incidence in Ret mice lacking gd T cells.…”