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Decreased NK-cell tumour immunosurveillance consequent to JAK inhibition enhances metastasis in breast cancer models

Author

Listed:
  • Alessia Bottos

    (Friedrich Miescher Institute for Biomedical Research)

  • Dagmar Gotthardt

    (Institute of Pharmacology and Toxicology, University of Veterinary Medicine)

  • Jason W. Gill

    (Friedrich Miescher Institute for Biomedical Research)

  • Albana Gattelli

    (Friedrich Miescher Institute for Biomedical Research)

  • Anna Frei

    (Friedrich Miescher Institute for Biomedical Research
    University of Basel)

  • Alexandar Tzankov

    (Institute of Pathology, University Hospital Basel)

  • Veronika Sexl

    (Institute of Pharmacology and Toxicology, University of Veterinary Medicine)

  • Aleksandra Wodnar-Filipowicz

    (Stem Cell Center of Competence, University of Basel)

  • Nancy E. Hynes

    (Friedrich Miescher Institute for Biomedical Research
    University of Basel)

Abstract

The JAK/STAT pathway is an attractive target for breast cancer therapy due to its frequent activation, and clinical trials evaluating JAK inhibitors (JAKi) in advanced breast cancer are ongoing. Using patient biopsies and preclinical models of breast cancer, we demonstrate that the JAK/STAT pathway is active in metastasis. Unexpectedly, blocking the pathway with JAKi enhances the metastatic burden in experimental and orthotopic models of breast cancer metastasis. We demonstrate that this prometastatic effect is due to the immunosuppressive activity of JAKi with ensuing impairment of NK-cell-mediated anti-tumour immunity. Furthermore, we show that immunostimulation with IL-15 overcomes the enhancing effect of JAKi on metastasis formation. Our findings highlight the importance of evaluating the effect of targeted therapy on the tumour environment. The impact of JAKi on NK cells and the potential value of immunostimulators to overcome the weakened tumour immunosurveillance, are worthwhile considering in the clinical setting of breast cancer.

Suggested Citation

  • Alessia Bottos & Dagmar Gotthardt & Jason W. Gill & Albana Gattelli & Anna Frei & Alexandar Tzankov & Veronika Sexl & Aleksandra Wodnar-Filipowicz & Nancy E. Hynes, 2016. "Decreased NK-cell tumour immunosurveillance consequent to JAK inhibition enhances metastasis in breast cancer models," Nature Communications, Nature, vol. 7(1), pages 1-12, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12258
    DOI: 10.1038/ncomms12258
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    Cited by:

    1. Jing Bi & Zhihui Wu & Xin Zhang & Taoling Zeng & Wanjun Dai & Ningyuan Qiu & Mingfeng Xu & Yikai Qiao & Lang Ke & Jiayi Zhao & Xinyu Cao & Qi Lin & Xiao Lei Chen & Liping Xie & Zhong Ouyang & Jujiang , 2023. "TMEM25 inhibits monomeric EGFR-mediated STAT3 activation in basal state to suppress triple-negative breast cancer progression," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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