title: IFN-γ is required for cytotoxic T cell-dependent cancer genome immunoediting.
abstract: Genetic evolution that occurs during cancer progression enables tumour heterogeneity, thereby fostering tumour adaptation, therapeutic resistance and metastatic potential. Immune responses are known to select (immunoedit) tumour cells displaying immunoevasive properties. Here we address the role of IFN-γ in mediating the immunoediting process. We observe that, in several mouse tumour models such as HA-expressing 4T1 mammary carcinoma cells, OVA-expressing EG7 lymphoma cells and CMS5 MCA-induced fibrosarcoma cells naturally expressing mutated extracellular signal-regulated kinase (ERK) antigen, the action of antigen-specific cytotoxic T cell (CTL) in vivo results in the emergence of resistant cancer cell clones only in the presence of IFN-γ within the tumour microenvironment. Moreover, we show that exposure of tumours to IFN-γ-producing antigen-specific CTLs in vivo results in copy-number alterations (CNAs) associated with DNA damage response and modulation of DNA editing/repair gene expression. These results suggest that enhanced genetic instability might be one of the mechanisms by which CTLs and IFN-γ immunoedits tumours, altering their immune resistance as a result of genetic evolution.
authors.affiliation: Division of Cell Biology, Biomedical Research Center, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo 113-8421, Japan.|Department of Biofunctional Micribiota, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo 113-8421, Japan.|Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.|Cancer Immunology Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, 3002 Victoria, Australia.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Sendai 980-8578, Japan.|Department of Immunobiology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai 980-8575, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Nakayama
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, 3002 Victoria, Australia.|Division of Pathogenic Biochemistry, Department of Bioscience, Institute of Natural Medicine, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hayakawa
authors.affiliation: Laboratory of Morphology and Image Analysis, Biomedical Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kojima
authors.affiliation: Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.|Department of Oncology, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ikeda
authors.affiliation: Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.|Department of Hematology and Oncology, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, New York 10029, USA.
authors.forename: Naoko
authors.initials: N
authors.lastname: Imai
authors.affiliation: Department of Immunobiology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai 980-8575, Japan.
authors.forename: Kouetsu
authors.initials: K
authors.lastname: Ogasawara
authors.affiliation: Department of Biofunctional Micribiota, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo 113-8421, Japan.|Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.|Atopy (Allergy) Research Center, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.affiliation: Cancer Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Thomas
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, 3002 Victoria, Australia.|Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, 4006 Queensland, Australia.|School of Medicine, University of Queensland, Herston, 4006 Queensland, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D004249:DNA Damage / Q000276:immunology; D004260:DNA Repair / Q000276:immunology; D018450:Disease Progression; D019143:Evolution, Molecular; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000276:immunology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D042822:Genomic Instability / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000951:Antigens, Neoplasm; D007371:Interferon-gamma; D048049:Extracellular Signal-Regulated MAP Kinases