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

Author

Listed:
  • Kazuyoshi Takeda

    (Biomedical Research Center, Graduate School of Medicine, Juntendo University
    Graduate School of Medicine, Juntendo University
    Juntendo University School of Medicine
    Cancer Immunology Program, Peter MacCallum Cancer Centre, St Andrews Place)

  • Masafumi Nakayama

    (Frontier Research Institute for Interdisciplinary Sciences, Tohoku University
    Institute of Development, Aging, and Cancer, Tohoku University)

  • Yoshihiro Hayakawa

    (Cancer Immunology Program, Peter MacCallum Cancer Centre, St Andrews Place
    Institute of Natural Medicine, University of Toyama, Sugitani 2630)

  • Yuko Kojima

    (Laboratory of Morphology and Image Analysis, Biomedical Research Center, Juntendo University Graduate School of Medicine)

  • Hiroaki Ikeda

    (Mie University Graduate School of Medicine, 2-174 Edobashi
    Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto)

  • Naoko Imai

    (Mie University Graduate School of Medicine, 2-174 Edobashi
    Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue)

  • Kouetsu Ogasawara

    (Institute of Development, Aging, and Cancer, Tohoku University)

  • Ko Okumura

    (Graduate School of Medicine, Juntendo University
    Juntendo University School of Medicine
    Atopy (Allergy) Research Center, Graduate School of Medicine, Juntendo University)

  • David M. Thomas

    (Garvan Institute of Medical Research)

  • Mark J. Smyth

    (Cancer Immunology Program, Peter MacCallum Cancer Centre, St Andrews Place
    Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute
    School of Medicine, University of Queensland)

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.

Suggested Citation

  • Kazuyoshi Takeda & Masafumi Nakayama & Yoshihiro Hayakawa & Yuko Kojima & Hiroaki Ikeda & Naoko Imai & Kouetsu Ogasawara & Ko Okumura & David M. Thomas & Mark J. Smyth, 2017. "IFN-γ is required for cytotoxic T cell-dependent cancer genome immunoediting," Nature Communications, Nature, vol. 8(1), pages 1-13, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14607
    DOI: 10.1038/ncomms14607
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    Cited by:

    1. Rebecca J. Austin & Jasmin Straube & Rohit Halder & Yashaswini Janardhanan & Claudia Bruedigam & Matthew Witkowski & Leanne Cooper & Amy Porter & Matthias Braun & Fernando Souza-Fonseca-Guimaraes & Si, 2023. "Oncogenic drivers dictate immune control of acute myeloid leukemia," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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