Tumor-derived IL-35 promotes tumor growth by enhancing myeloid cell accumulation and angiogenesis.

Abstract

IL-35 is a member of the IL-12 family of cytokines that is comprised of an IL-12 p35 subunit and an 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 was demonstrated to be produced by regulatory T cells, gene-expression analysis revealed that it is likely to have a wider distribution, including expression in cancer cells. In this study, we demonstrated that IL-35 is produced in human cancer tissues, such as large B cell lymphoma, nasopharyngeal carcinoma, and melanoma. 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 it stimulates tumorigenesis in both immune-competent and Rag1/2-deficient mice. Tumor-derived IL-35 increases CD11b(+)Gr1(+) myeloid cell accumulation in the 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 Ag-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 for IL-35 in promoting tumor growth via the enhancement of myeloid cell accumulation, tumor angiogenesis, and suppression of tumor immunity.

DOI: 10.4049/jimmunol.1202535
05020132014201520162017
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@article{Wang2013TumorderivedIP, title={Tumor-derived IL-35 promotes tumor growth by enhancing myeloid cell accumulation and angiogenesis.}, author={Zhihui Wang and Jin-Qing Liu and Zhenzhen Liu and Rulong Shen and Guoqiang Zhang and Jianping Xu and Sujit Basu and Youmei Feng and Xue-Feng Bai}, journal={Journal of immunology}, year={2013}, volume={190 5}, pages={2415-23} }