title: 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.affiliation: Department of Veterinary Medicine, National Taiwan University, Taipei, Taiwan, Republic of China.
authors.forename: Ya-Wen
authors.initials: YW
authors.lastname: Hsiao
authors.forename: Kuang-Wen
authors.initials: KW
authors.lastname: Liao
authors.forename: Shao-Wen
authors.initials: SW
authors.lastname: Hung
authors.forename: Rea-Min
authors.initials: RM
authors.lastname: Chu
mesh_terms: D000276:Adjuvants, Immunologic / Q000378:metabolism / Q000502:physiology; D000818:Animals; D002474:Cell-Free System / Q000276:immunology / Q000378:metabolism; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D018450:Disease Progression; D004285:Dogs; D005260:Female; D015850:Interleukin-6 / Q000096:biosynthesis / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology* / Q000378:metabolism; D016131:Lymphocyte Subsets / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009000:Monocytes / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009365:Neoplasm Regression, Spontaneous / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D013491:Suppressor Factors, Immunologic / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured; D014685:Venereal Tumors, Veterinary / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*
chemical_list: D000276:Adjuvants, Immunologic; D015850:Interleukin-6; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D013491:Suppressor Factors, Immunologic; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1