Article

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

Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon, Korea.
Cancer Research (Impact Factor: 9.28). 06/2008; 68(10):3915-23. DOI: 10.1158/0008-5472.CAN-08-0206
Source: PubMed

ABSTRACT Overexpression of the immunosuppressive cytokine transforming growth factor beta (TGF-beta) 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-beta. 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-beta and IL-6 in vitro. Treatment of mice with anti-TGF-beta 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-beta may actively subvert the CD8+ arm of the immune system into directly promoting tumor growth by an IL-17-dependent mechanism.

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    • "On the other hand, TGFβ suppresses both innate and adaptive immune responses in the tumor microenvironment. CTL-mediated tumor elimination is thus reduced by the presence of TGFβ [32,33]. As both 3M-052 and CpG ODN tend to reduce the level of immune suppression in the tumor microenvironment, their effect on CTLA-4 and TGFβ expression was examined. "
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    • "Indeed in our previous publications, we have shown that BC-associated metastasis is significantly augmented in mice with arthritis and that IL-17A, IL-6, COX-2, VEGF, MMP-9, IGF-II, M-CSF and TNF-α are all major players [6,7]. These cytokines not only play an imperative role in arthritis but also cancer development and progression [37-48]. "
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    • "Roberts et al. [29] found that CD8+ T cells could also promote the cutaneous carcinogenesis using a two-step chemical initiation/promotion protocol (DMBA and TPA). A DMBA/TPA carcinogenic regimen could up-regulate the expressions of TGF-β and IL-6, resulting in Tc17 cell skewing [30], [31]. Besides, they also found that a subset of tumor-promoting IL-17+CD8+ cell population might exist in this model. "
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