title: IL-27 enhances the expression of TRAIL and TLR3 in human melanomas and inhibits their tumor growth in cooperation with a TLR3 agonist poly(I:C) partly in a TRAIL-dependent manner.
abstract: Interleukin (IL)-27 is a member of the IL-6/IL-12 cytokine family and possesses potent antitumor activity, which is mediated by multiple mechanisms. Toll-like receptor (TLR)3 is the critical sensor of the innate immune system that serves to identify viral double-stranded RNA. TLR3 is frequently expressed by various types of malignant cells, and recent studies reported that a synthetic TLR3 agonist, polyinosinic-polycytidylic acid [poly(I:C)], induces antitumor effects on malignant cells. In the present study, we have explored the effect of IL-27 on human melanomas and uncovered a previously unknown mechanism. We found that IL-27 inhibits in vitro tumor growth of human melanomas and greatly enhances the expression of TNF-related apoptosis inducing ligand (TRAIL) in a dose-dependent manner. Neutralizing antibody against TRAIL partly but significantly blocked the IL-27-mediated inhibition of tumor growth. In addition, IL-27 and poly(I:C) cooperatively augmented TRAIL expression and inhibited tumor growth. The cooperative effect could be ascribed to the augmented expression of TLR3, but not retinoic acid-inducible gene-I or anti-melanoma differentiation-associated gene 5, by IL-27. The inhibition of tumor growth by the combination was also significantly abrogated by anti-TRAIL neutralizing antibody. Moreover, IL-27 and poly(I:C) cooperatively suppressed in vivo tumor growth of human melanoma in immunodeficient mice. Taken together, these results suggest that IL-27 enhances the expression of TRAIL and TLR3 in human melanomas and inhibits their tumor growth in cooperation with poly(I:C), partly in a TRAIL-dependent manner. Thus, IL-27 and the combination of IL-27 and poly(I:C) may be attractive candidates for cancer immunotherapy.
authors.affiliation: Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan.
authors.forename: Yukino
authors.initials: Y
authors.lastname: Chiba
authors.forename: Izuru
authors.initials: I
authors.lastname: Mizoguchi
authors.forename: Kana
authors.initials: K
authors.lastname: Mitobe
authors.forename: Kaname
authors.initials: K
authors.lastname: Higuchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagai
authors.forename: Chikako
authors.initials: C
authors.lastname: Nishigori
authors.forename: Junichiro
authors.initials: J
authors.lastname: Mizuguchi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yoshimoto
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D064094:Interleukin-27 / Q000494:pharmacology*; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008954:Models, Biological; D011070:Poly I-C / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D051196:Toll-Like Receptor 3 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*
chemical_list: D064094:Interleukin-27; C495344:TLR3 protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; D051196:Toll-Like Receptor 3; D011070:Poly I-C