Tumor-infiltrating lymphocyte secretion of IL-6 antagonizes tumor-derived TGF-beta 1 and restores the lymphokine-activated killing activity.

Abstract

IL-6 is a multifunctional cytokine that regulates cell growth, differentiation, and cell survival. Many tumor cells produce TGF-beta1, which allows them to evade CTL-mediated immune responses. IL-6 antagonizes TGF-beta1 inhibition of CD3 cell activation. However, whether IL-6 restores NK activity, which also is suppressed by TGF-beta1, is not known. We used canine transmissible venereal tumor (CTVT), which produces TGF-beta1, as a model to determine whether IL-6 restores lymphokine-activated killer (LAK) activity. During the progression phase, CTVT cells stop expressing MHC molecules. During the regression phase, the number of surface MHC molecules increases dramatically on about one-third of tumor cells. Tumor cells that stop expressing MHC should be targeted by NK cells. In this study, we found that TGF-beta1 secreted by CTVT cells suppressed LAK cytotoxicity. Interestingly, tumor-infiltrating lymphocytes (TIL) isolated from regressing CTVT secrete high concentrations of IL-6 and antagonize the anti-LAK activity of tumor cell TGF-beta1. TIL also produce IL-6 during progression phase, but the concentration is too low to block the anti-LAK activity of TGF-beta1. There is probably a threshold concentration of IL-6 needed to reverse TGF-beta1-inhibited LAK activity. In addition, in the absence of TGF-beta1, IL-6 derived from TIL does not promote the activity of LAK. This new mechanism, in which TIL manufacture high concentrations of IL-6 to block tumor TGF-beta1 anti-LAK activity, has potential applications in cancer immunotherapy and tumor prognosis.

• Authors: Ya-Wen Hsiao, Kuang-Wen Liao, Shao-Wen Hung, Rea-Min Chu
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 172 Issue 3 Pg. 1508-14 (Feb 01 2004) ISSN: 0022-1767 [Print] United States
• PMID: 14734728 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adjuvants, Immunologic
• Interleukin-6
• Neoplasm Proteins
• RNA, Messenger
• Suppressor Factors, Immunologic
• Transforming Growth Factor beta
• Transforming Growth Factor beta1

Topics

• Adjuvants, Immunologic (metabolism, physiology)
• Animals
• Cell-Free System (immunology, metabolism)
• Coculture Techniques
• Cytotoxicity, Immunologic (immunology)
• Disease Progression
• Dogs
• Female
• Interleukin-6 (biosynthesis, metabolism, pharmacology, physiology)
• Intracellular Fluid (immunology, metabolism)
• Killer Cells, Lymphokine-Activated (immunology, metabolism)
• Lymphocyte Subsets (pathology)
• Lymphocytes, Tumor-Infiltrating (immunology, metabolism, pathology)
• Male
• Monocytes (pathology)
• Neoplasm Proteins (antagonists & inhibitors)
• Neoplasm Regression, Spontaneous (immunology)
• RNA, Messenger (biosynthesis)
• Suppressor Factors, Immunologic (antagonists & inhibitors, metabolism, physiology)
• Transforming Growth Factor beta (antagonists & inhibitors, biosynthesis, genetics, physiology)
• Transforming Growth Factor beta1
• Tumor Cells, Cultured
• Venereal Tumors, Veterinary (immunology, metabolism, therapy)