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: Jeong-Seok Nam, Masaki Terabe, Mi-Jin Kang, Helen Chae, Nga Voong, Yu-An Yang, Arian Laurence, Aleksandra Michalowska, Mizuko Mamura, Scott Lonning, Jay A Berzofsky, Lalage M Wakefield
• Journal: Cancer research (Cancer Res) Vol. 68 Issue 10 Pg. 3915-23 (May 15 2008) ISSN: 1538-7445 [Electronic] United States
• PMID: 18483277 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Interleukin-17
• Transforming Growth Factor beta

Topics

• Animals
• CD4-Positive T-Lymphocytes (metabolism)
• CD8-Positive T-Lymphocytes (metabolism)
• Cell Line, Tumor
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Interleukin-17 (physiology)
• Lymph Nodes (pathology)
• Mice
• Mice, Inbred BALB C
• Neoplasm Transplantation
• Neoplasms (immunology, metabolism)
• Rats
• Transforming Growth Factor beta (metabolism)