Transforming Growth Factor β Subverts the Immune System into Directly Promoting Tumor Growth through Interleukin-17

Abstract

Overexpression of the immunosuppressive cytokine transforming growth factor B (TGF-B) is one strategy that tumors have developed to evade effective immunesurveillance. Using transplantable models of breast and colon cancer, we made the unexpected finding that CD8+ cells in tumor-bearing animals can directly promote tumorigenesis, by a mechanism that is dependent on TGF-B. We showed that CD8+ splenocytes from tumor-bearing mice expressed elevated interleukin (IL)-17 when compared with naive mice, and that CD8+ T cells could be induced to make IL-17 on addition of TGF-B and IL-6 in vitro. Treatment of mice with anti-TGF-B antibodies in vivo reduced IL-17 expression both in the tumor and the locoregional lymph nodes. Although IL-17 has not previously been shown to act as a survival factor for epithelial cells, we found that IL-17 suppressed apoptosis of several tumor cell lines in vitro, suggesting that this altered T-cell polarization has the potential to promote tumorigenesis directly, rather than indirectly through inflammatory sequelae. Consistent with this hypothesis, knockdown of the IL-17 receptor in 4T1 mouse mammary cancer cells enhanced apoptosis and decreased tumor growth in vivo. Thus, in addition to suppressing immune surveillance, tumor-induced TGF-B may actively subvert the CD8+ arm of the immune system into directly promoting tumor growth by an IL-17-dependent mechanism. [Cancer Res 2008;68(10):3915-23]

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

“…Consistent with this finding, prior studies have shown that substantial IL-17 expression levels in human cancer tissues were correlated with increased vascularity [4,5]. Moreover, our findings are consistent with other reports that IL-17 directly influenced on the proliferation and survival of tumor cells and that IL-6-STAT3 pathway promoted tumor growth in IL-17-dependent manner [34,43]. However, it is an unresolved controversial issue whether IL-17 acts as a pro-or anti-tumor agent.…”

“…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.…”

“…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.…”

“…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.In this paper, we demonstrate that (i) IL-17 is a pro-tumor cytokine, which supports tumor growth by promoting angiogenesis; (ii) gd T cells, but neither TCRabCD4 1 T cells nor TCRabCD8 1 T cells, are the major cellular source of IL-17 in tumor-infiltrating lymphocytes (TIL); (iii) blood circulating gd T cells, but not skin-resident Vg5 1 gd T cells, infiltrate into the tumor site; (iv) tumor-infiltrating gd T cells differentiate into IL-17-producing cells but downmodulate their cytotoxic activity within the tumor microenvironment; (v) IL-17 produced by tumor-infiltrating gd T cells promotes tumor progression by inducing angiogenesis. Thus, this paper proposes the novel concept that IL-17-producing gd T cells play a crucial role as tumor-promoting T cells during tumor development.…”

“…40: 1927Immunol. -1937 Cellular immune responsewww.eji-journal.eu models [28][29][30][31][32][33][34][35]. However, the previous studies have not examined a pro-tumor function of gd T cells.…”