title: Immature myeloid cells directly contribute to skin tumor development by recruiting IL-17-producing CD4+ T cells.
abstract: Evidence links chronic inflammation with cancer, but cellular mechanisms involved in this process remain unclear. We have demonstrated that in humans, inflammatory conditions that predispose to development of skin and colon tumors are associated with accumulation in tissues of CD33+S100A9+ cells, the phenotype typical for myeloid-derived suppressor cells in cancer or immature myeloid cells (IMCs) in tumor-free hosts. To identify the direct role of these cells in tumor development, we used S100A9 transgenic mice to create the conditions for topical accumulation of these cells in the skin in the absence of infection or tissue damage. These mice demonstrated accumulation of granulocytic IMCs in the skin upon topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA), resulting in a dramatic increase in the formation of papillomas during epidermal carcinogenesis. The effect of IMCs on tumorigenesis was not associated with immune suppression, but with CCL4 (chemokine [C-C motif] ligand 4)-mediated recruitment of IL-17-producing CD4+ T cells. This chemokine was released by activated IMCs. Elimination of CD4+ T cells or blockade of CCL4 or IL-17 abrogated the increase in tumor formation caused by myeloid cells. Thus, this study implicates accumulation of IMCs as an initial step in facilitation of tumor formation, followed by the recruitment of CD4+ T cells.
authors: H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612.
authors: Myrna L
authors: ML
authors: Ortiz
authors: The Wistar Institute, Philadelphia, PA 19104.
authors: Vinit
authors: V
authors: Kumar
authors: H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 Sahlgrenska Cancer Center, University of Gothenburg, S-405 30 Gothenburg, Sweden.
authors: Anna
authors: A
authors: Martner
authors: The Wistar Institute, Philadelphia, PA 19104.
authors: Sridevi
authors: S
authors: Mony
authors: The Wistar Institute, Philadelphia, PA 19104.
authors: Laxminarasimha
authors: L
authors: Donthireddy
authors: The Wistar Institute, Philadelphia, PA 19104.
authors: Thomas
authors: T
authors: Condamine
authors: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors: John
authors: J
authors: Seykora
authors: Antigen Presentation Research Group, Imperial College London, London HA1 3UJ, England, UK.
authors: Stella C
authors: SC
authors: Knight
authors: Antigen Presentation Research Group, Imperial College London, London HA1 3UJ, England, UK St. Mark's Hospital, Harrow HA1 3UJ, England, UK.
authors: George
authors: G
authors: Malietzis
authors: Antigen Presentation Research Group, Imperial College London, London HA1 3UJ, England, UK St. Mark's Hospital, Harrow HA1 3UJ, England, UK.
authors: Gui Han
authors: GH
authors: Lee
authors: St. Mark's Hospital, Harrow HA1 3UJ, England, UK.
authors: Morgan
authors: M
authors: Moorghen
authors: H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 Sahlgrenska Cancer Center, University of Gothenburg, S-405 30 Gothenburg, Sweden.
authors: Brianna
authors: B
authors: Lenox
authors: H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612.
authors: Noreen
authors: N
authors: Luetteke
authors: Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Augusta, GA 30912.
authors: Esteban
authors: E
authors: Celis
authors: The Wistar Institute, Philadelphia, PA 19104 dgabrilovich@wistar.org.
authors: Dmitry
authors: D
authors: Gabrilovich
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D040502:Calgranulin B / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D054407:Chemokine CCL4 / Q000378:metabolism; D003092:Colitis / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D012878:Skin Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000633:toxicity
chemical_list: C554292:12-O-tetradecanoylphorbol-1,3-acetate; D040502:Calgranulin B; D054407:Chemokine CCL4; D013755:Tetradecanoylphorbol Acetate