title: IL-17 enhances tumor development in carcinogen-induced skin cancer.
abstract: Inflammatory conditions elicited by extrinsic environmental factors promote malignant cell transformation, tumor growth, and metastasis. Although most attention has been focused on innate immune mechanisms of inflammatory carcinogenesis, more recently the role of T cells in cancer promotion has been examined. Although IFN-dependent Th1 responses that promote Stat1 signaling inhibit tumor growth, the role of T helper type 17 responses, and interleukin-17 (IL-17) in particular, has been controversial. Indeed, IL-17 has been reported to either enhance or inhibit the growth of transplantable tumors, depending on the system. Little is known about the role of IL-17 in de novo carcinogenesis. Using IL-17 knockout mice, we examined the role of IL-17 in the classic DMBA/TPA-induced skin carcinogenesis model. Disruption of IL-17 dramatically reduced tumorigenesis in this model in a manner correlated with diminished Stat3 activation in the tumor microenvironment. IL-17 loss reduced Stat3-associated proliferative and antiapoptotic gene expression along with epidermal cell proliferation and hyperplasia. In addition, IL-17 loss was associated with reduced expression of Stat3-regulated chemokines that attract myeloid cells and a decreased infiltration of myeloid cells into the local tumor microenvironment. Together, our findings point to a critical role of the IL-17-Stat3 pathway in supporting cancer-associated inflammation in the tumor microenvironment. Therapeutic approaches that target this pathway may therefore be effective to inhibit carcinogenesis.
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute at City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Tangsheng
authors.initials: T
authors.lastname: Yi
authors.forename: Wang
authors.initials: W
authors.lastname: Zhang
authors.forename: Drew M
authors.initials: DM
authors.lastname: Pardoll
authors.forename: Hua
authors.initials: H
authors.lastname: Yu
mesh_terms: D000814:Aniline Compounds; D000818:Animals; D039481:CD11b Antigen; D002273:Carcinogens; D048708:Cell Growth Processes / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D020381:Interleukin-17 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000473:pathology; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate; D059016:Tumor Microenvironment
chemical_list: D000814:Aniline Compounds; D039481:CD11b Antigen; D002273:Carcinogens; D020381:Interleukin-17; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C050795:N,N-dimethyl-4-anisidine; D007371:Interferon-gamma; D013755:Tetradecanoylphorbol Acetate