Tumor-derived IL-35 promotes tumor growth by enhancing myeloid cell accumulation and angiogenesis (P2034)

Abstract

Abstract IL-35 is a member of the IL-12 family of cytokines consisting of IL-12 p35 subunit and IL-12 p40-related protein subunit, EBV-induced gene 3 (EBI3). IL-35 functions through IL-35R and has a potent immune suppressive activity. Although IL-35 has been demonstrated to be produced by regulatory T cells, gene expression analysis has revealed that IL-35 is likely to have wider distribution including expression in cancer cells. In this study we have demonstrated that IL-35 is produced in human cancer tissues such as large B cell lymphoma, nasopharyngeal carcinoma and melanoma. In order to determine the roles of tumor-derived IL-35 in tumorigenesis and tumor immunity, we generated IL-35 producing plasmacytoma J558 and B16 melanoma cells, and observed that the expression of IL-35 in cancer cells does not affect their growth and survival in vitro, but stimulates tumorigenesis in both immune competent and Rag1/2 deficient mice. Tumor-derived IL-35 increases CD11b+Gr1+ myeloid cell homing in tumor microenvironment, and thereby promotes tumor angiogenesis. In immune competent mice, spontaneous CTL responses to tumors are diminished. IL-35 does not directly inhibit tumor antigen specific CD8+ T cell activation, differentiation and effector functions. However, IL-35-treated cancer cells had increased expression of gp130 and reduced sensitivity to CTL destruction. Thus, our study indicates novel functions of IL-35 in promoting tumor growth via enhancing myeloid cell accumulation, tumor angiogenesis and suppression of tumor immunity.