title: Transforming growth factor beta subverts the immune system into directly promoting tumor growth through interleukin-17.
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.
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon, Korea.
authors.forename: Jeong-Seok
authors.initials: JS
authors.lastname: Nam
authors.forename: Masaki
authors.initials: M
authors.lastname: Terabe
authors.forename: Mi-Jin
authors.initials: MJ
authors.lastname: Kang
authors.forename: Helen
authors.initials: H
authors.lastname: Chae
authors.forename: Nga
authors.initials: N
authors.lastname: Voong
authors.forename: Yu-An
authors.initials: YA
authors.lastname: Yang
authors.forename: Arian
authors.initials: A
authors.lastname: Laurence
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Michalowska
authors.forename: Mizuko
authors.initials: M
authors.lastname: Mamura
authors.forename: Scott
authors.initials: S
authors.lastname: Lonning
authors.forename: Jay A
authors.initials: JA
authors.lastname: Berzofsky
authors.forename: Lalage M
authors.initials: LM
authors.lastname: Wakefield
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020381:Interleukin-17 / Q000502:physiology*; D008198:Lymph Nodes / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism*; D051381:Rats; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D020381:Interleukin-17; D016212:Transforming Growth Factor beta