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Cancer Research 68, 3915, May 15, 2008. doi: 10.1158/0008-5472.CAN-08-0206
© 2008 American Association for Cancer Research

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Immunology

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

Jeong-Seok Nam1,2, Masaki Terabe3, Mi-Jin Kang2, Helen Chae2, Nga Voong2, Yu-an Yang2, Arian Laurence4, Aleksandra Michalowska2, Mizuko Mamura1,2, Scott Lonning5, Jay A. Berzofsky3 and Lalage M. Wakefield2

1 Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon, Korea; 2 Laboratory of Cancer Biology and Genetics; 3 Vaccine Branch, National Cancer Institute; and 4 Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland; and 5 Genzyme Corp, Framingham, Massachusetts

Requests for reprints: Lalage Wakefield, National Cancer Institute, Building 37, Room 4032A, 37 Convent Drive, MSC 4255, Bethesda, MD 20892-4255. Phone: 301-496-8351; Fax: 301-496-8709; E-mail: lw34g{at}nih.gov.

Key Words: IL-17TGF-β • immune surveillance • cancer • mouse models

Overexpression of the immunosuppressive cytokine transforming growth factor β (TGF-β) 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-β. 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-β and IL-6 in vitro. Treatment of mice with anti–TGF-β 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-β 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]




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Copyright © 2008 by the American Association for Cancer Research.