title: Decreased NK-cell tumour immunosurveillance consequent to JAK inhibition enhances metastasis in breast cancer models.
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.
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.
authors.forename: Alessia
authors.initials: A
authors.lastname: Bottos
authors.affiliation: Institute of Pharmacology and Toxicology, Department for Biomedical Sciences, University of Veterinary Medicine, 1210 Vienna, Austria.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Gotthardt
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.
authors.forename: Jason W
authors.identifier: 0000-0003-0955-6470
authors.initials: JW
authors.lastname: Gill
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.
authors.forename: Albana
authors.initials: A
authors.lastname: Gattelli
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.|University of Basel, CH-4002 Basel, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Frei
authors.affiliation: Institute of Pathology, University Hospital Basel, CH-4031 Basel, Switzerland.
authors.forename: Alexandar
authors.identifier: 0000-0002-1100-3819
authors.initials: A
authors.lastname: Tzankov
authors.affiliation: Institute of Pharmacology and Toxicology, Department for Biomedical Sciences, University of Veterinary Medicine, 1210 Vienna, Austria.
authors.forename: Veronika
authors.initials: V
authors.lastname: Sexl
authors.affiliation: Stem Cell Center of Competence, University of Basel, CH-4002 Basel, Switzerland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Wodnar-Filipowicz
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.|University of Basel, CH-4002 Basel, Switzerland.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Hynes
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000556:secondary*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D007157:Immunologic Surveillance / Q000187:drug effects; D056747:Immunomodulation / Q000187:drug effects; D019409:Interleukin-15 / Q000494:pharmacology; D000075242:Janus Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D053612:Janus Kinases / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008954:Models, Biological; D050791:STAT Transcription Factors / Q000378:metabolism
chemical_list: D019409:Interleukin-15; D000075242:Janus Kinase Inhibitors; D050791:STAT Transcription Factors; D053612:Janus Kinases