title: Acquisition of an immunosuppressive protumorigenic macrophage phenotype depending on c-Jun phosphorylation.
abstract: The inflamed tumor microenvironment plays a critical role in tumorigenesis. However, the mechanisms through which immune cells, particularly macrophages, promote tumorigenesis have only been partially elucidated, and the full scope of signaling pathways supplying macrophages with protumorigenic phenotypes still remain largely unknown. Here we report that germ-line absence of c-Jun N-terminal phosphorylation at serines 63 and 73 impedes inflammation-associated hepatocarcinogenesis, yet deleting c-Jun only in hepatocytes does not inhibit hepatocellular carcinoma (HCC) formation. Moreover, in human HCC-bearing livers, c-Jun phosphorylation is found in inflammatory cells, whereas it is mostly absent from malignant hepatocytes. Interestingly, macrophages in livers of mice with chronic hepatitis gradually switch their phenotype along the course of disease. Macrophage phenotype and density are dictated by c-Jun phosphorylation, in vitro and in vivo. Transition of macrophage phenotype, from antitumorigenic to protumorigenic, occurs before tumorigenesis, resulting in the production of various chemokines, including chemokine (C-C motif) ligand 17 (CCL17) and CCL22. Such signals, emanating from the liver microenvironment, direct the recruitment of regulatory T cells, which are known to facilitate HCC growth. Our findings identify c-Jun phosphorylation as a key mediator of macrophage education and point to the recruitment of immunosuppressive regulatory T cells as a possible protumorigenic mechanism.
authors.affiliation: Department of Immunology and Cancer Research, Institute for Medical Research Israel Canada (IMRIC), Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel; Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel;
authors.forename: Simona
authors.initials: S
authors.lastname: Hefetz-Sela
authors.affiliation: Department of Immunology and Cancer Research, Institute for Medical Research Israel Canada (IMRIC), Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel; Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel;
authors.forename: Ilan
authors.initials: I
authors.lastname: Stein
authors.affiliation: Department of Immunology and Cancer Research, Institute for Medical Research Israel Canada (IMRIC), Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel;
authors.forename: Yair
authors.initials: Y
authors.lastname: Klieger
authors.affiliation: Department of Immunology and Cancer Research, Institute for Medical Research Israel Canada (IMRIC), Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel; Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel;
authors.forename: Rinnat
authors.initials: R
authors.lastname: Porat
authors.affiliation: Department of Immunology and Cancer Research, Institute for Medical Research Israel Canada (IMRIC), Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel;
authors.forename: Moshe
authors.initials: M
authors.lastname: Sade-Feldman
authors.affiliation: Department of Immunology and Cancer Research, Institute for Medical Research Israel Canada (IMRIC), Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel; Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel;
authors.forename: Farid
authors.initials: F
authors.lastname: Zreik
authors.affiliation: Division of Hematology, Chaim Sheba Medical Center, Tel-Hashomer 52621, Israel;
authors.forename: Arnon
authors.initials: A
authors.lastname: Nagler
authors.affiliation: Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel;
authors.forename: Orit
authors.initials: O
authors.lastname: Pappo
authors.affiliation: Institute of Pathology, University Hospital Basel, 4003 Basel, Switzerland;
authors.forename: Luca
authors.initials: L
authors.lastname: Quagliata
authors.affiliation: Biozentrum, University of Basel, CH4056 Basel, Switzerland;
authors.forename: Eva
authors.initials: E
authors.lastname: Dazert
authors.affiliation: Department of Internal Medicine I, Comprehensive Cancer Center, Institute for Cancer Research, Medical University of Vienna, A-1090 Vienna, Austria; and.
authors.forename: Robert
authors.initials: R
authors.lastname: Eferl
authors.affiliation: Institute of Pathology, University Hospital Basel, 4003 Basel, Switzerland;
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.affiliation: Cancer Cell Biology Programme, Spanish National Cancer Research Centre, E-28029 Madrid, Spain.
authors.forename: Erwin F
authors.initials: EF
authors.lastname: Wagner
authors.affiliation: Department of Immunology and Cancer Research, Institute for Medical Research Israel Canada (IMRIC), Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel;
authors.forename: Yinon
authors.initials: Y
authors.lastname: Ben-Neriah
authors.affiliation: Department of Immunology and Cancer Research, Institute for Medical Research Israel Canada (IMRIC), Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel;
authors.forename: Michal
authors.initials: M
authors.lastname: Baniyash
authors.affiliation: Department of Immunology and Cancer Research, Institute for Medical Research Israel Canada (IMRIC), Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel; Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; peli@hadassah.org.il.
authors.forename: Eli
authors.initials: E
authors.lastname: Pikarsky
mesh_terms: D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D049109:Cell Proliferation; D018925:Chemokines / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006505:Hepatitis / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism; D008264:Macrophages / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D010766:Phosphorylation; D011379:Prognosis; D017434:Protein Structure, Tertiary; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: D018925:Chemokines; D016755:Proto-Oncogene Proteins c-jun
keywords: HCC; M1 macrophages; M2 macrophages; Tregs; c-Jun phosphorylation