RT Journal Article
SR Electronic
T1 Tumor-Derived IL-35 Promotes Tumor Growth by Enhancing Myeloid Cell Accumulation and Angiogenesis
JF The Journal of Immunology
JO J. Immunol.
FD American Association of Immunologists
SP 2415
OP 2423
DO 10.4049/jimmunol.1202535
VO 190
IS 5
A1 Wang, Zhihui
A1 Liu, Jin-Qing
A1 Liu, Zhenzhen
A1 Shen, Rulong
A1 Zhang, Guoqiang
A1 Xu, Jianping
A1 Basu, Sujit
A1 Feng, Youmei
A1 Bai, Xue-Feng
YR 2013
UL http://www.jimmunol.org/content/190/5/2415.abstract
AB 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.