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.
Highlights
Interleukin (IL)-27 is a heterodimeric cytokine belonging to the IL-6/IL-12 cytokine family and consists of an IL-12 p40-related protein, Epstein-Barr virus-induced gene 3, and an IL-12 p35related protein, p28 [1]
IL-27 inhibits tumor growth of human melanomas We previously demonstrated that mouse melanoma B16F10 cells are not responsive to IL-27 due to a lack of expression of one of the IL-27R subunits, WSX-1
Time course analyses revealed that IFN regulatory factor (IRF)-1 mRNA expression was rapidly induced in response to IL-27 and poly(I:C), which was followed by up-regulation of TLR3 and TNF-related apoptosis inducing ligand (TRAIL) (Fig. 3C). These results suggest that IL-27 enhances the expression of TLR3 and TRAIL probably through IRF-1 in human melanomas, which could account for the cooperative effect between IL-27 and poly(I:C)
Summary
Interleukin (IL)-27 is a heterodimeric cytokine belonging to the IL-6/IL-12 cytokine family and consists of an IL-12 p40-related protein, Epstein-Barr virus-induced gene 3, and an IL-12 p35related protein, p28 [1]. We and other groups previously reported that IL-27 has a potent ability to induce tumor-specific antitumor and protective immunity through cytotoxic T lymphocyte (CTL) and natural killer (NK) cells in colon carcinoma colon 26 [7,8] and neuroblastoma TBJ [9] lines. IL-27 was further demonstrated to exert antitumor activity against poorly immunogenic B16F10 melanoma, which is mediated through NK cells but not CTL [10], and against NK cell–resistant head and neck squamous cell carcinoma SCCVII through NK cell–mediated antibody-dependent cellular cytotoxicity (ADCC) [11]. IL-27 exerts antitumor activities through multiple mechanisms including CTL, NK cells, ADCC, anti-angiogenic activity, and direct antiproliferative activity depending on the characteristics of individual tumors
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