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

Kazuyoshi Takeda, Masafumi Nakayama, Yoshihiro Hayakawa, Yuko Kojima, Hiroaki Ikeda, Naoko Imai, Kouetsu Ogasawara, Ko Okumura, David M. Thomas, Mark J. Smyth

Research output: Contribution to journalArticlepeer-review

57 Citations (Scopus)

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.

Original languageEnglish
Article number14607
JournalNature communications
Volume8
DOIs
Publication statusPublished - 2017 Feb 24

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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