Tumor-derived IL-35 promotes tumor growth by enhancing myeloid cell accumulation and angiogenesis.
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.
Department of Pathology, The Ohio State University, Columbus, OH 43210, USA.
Zhihui
Z
Wang
Jin-Qing
JQ
Liu
Zhenzhen
Z
Liu
Rulong
R
Shen
Guoqiang
G
Zhang
Jianping
J
Xu
Sujit
S
Basu
Youmei
Y
Feng
Xue-Feng
XF
Bai
D000818:Animals; D039481:CD11b Antigen / Q000235:genetics / Q000276:immunology; D002277:Carcinoma; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D009389:Neovascularization, Pathologic; D010954:Plasmacytoma / Q000098:blood supply* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology
D039481:CD11b Antigen; C494200:Il6st protein, mouse; D007378:Interleukins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011956:Receptors, Cell Surface; C551746:granulocyte receptor 1, mouse; C569375:interleukin-35, mouse; D050822:Cytokine Receptor gp130