IFN-γ is required for cytotoxic T cell-dependent cancer genome immunoediting

• Published in: Nature communications Vol. 8; no. 1; p. 14607
• Main Authors: Takeda, Kazuyoshi, Nakayama, Masafumi, Hayakawa, Yoshihiro, Kojima, Yuko, Ikeda, Hiroaki, Imai, Naoko, Ogasawara, Kouetsu, Okumura, Ko, Thomas, David M., Smyth, Mark J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.02.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 13/31; 631/250/580; 631/67/69; Animals; Antigens, Neoplasm - genetics; Antigens, Neoplasm - immunology; Disease Progression; DNA Damage - immunology; DNA Repair - immunology; Evolution, Molecular; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - immunology; Female; Gene Expression Regulation, Neoplastic - immunology; Genomic Instability - immunology; Humanities and Social Sciences; Humans; Immune Tolerance - genetics; Interferon-gamma - genetics; Interferon-gamma - immunology; Interferon-gamma - metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; multidisciplinary; Mutation; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - pathology; Science; Science (multidisciplinary); T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism; Tumor Microenvironment - genetics; Tumor Microenvironment - immunology; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms14607

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. T cell mediated anti-tumour immune responses result in the emergence of an immune-resistant population in a process called immunoediting. Here, the authors show that immunoediting is associated with an increase in genomic rearrangements of tumour cells that requires both cytotoxic T cells and IFNγ exposure.