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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02065

Loss of Janus Associated Kinase 1 alters urothelial cell function and facilitates the development of bladder cancer

  • 1Hospital Universitario Son Espases, Spain
  • 2Complutense University of Madrid, Spain
  • 3Instituto de Investigación Sanitaria de Palma (IdISPa), Spain
  • 4University College London, United Kingdom
  • 5Royal Free Hospital, United Kingdom
  • 6University of York, United Kingdom
  • 7St James's University Hospital, United Kingdom
  • 8Great Ormond Street Hospital, United Kingdom

Inherited Primary Immunodeficiency (PID) disorders are associated with increased risk of malignancy that may relate to impaired antitumor immune responses or a direct role for PID germline mutations in tumorigenesis. We recently identified germline loss of function mutations in Janus Associated Kinase 1 (JAK1) causing primary immunodeficiency characterised by infections and associated with early onset, fatal high-grade bladder carcinoma. Somatic mutations in JAK1, required for immune cell signalling in response to interferon gamma (IFNγ), have been associated with several non-hematopoietic and hematopoietic cancer cell types but pathogenic mechanisms remain largely unexplored. Here we demonstrate that JAK1 is required for the intrinsic IFNγ response of urothelial cells impacting immunogenicity and cell survival. Specifically, JAK1-deficient urothelial cells showed reduced surface expression of major histocompatibility complex class II (MHC II), intercellular adhesion molecule-1 (ICAM-1) and programmed death-ligand-1 (PD-L1) after IFNγ stimulation and were resistant to IFNγ-induced apoptosis and lymphocyte-mediated killing. In addition, we identify a previously unknown role for IFNγ signalling in modulating urothelial differentiation. Together, our findings support a role for urothelial cell JAK1 in immune surveillance and development of bladder cancer. Our results have implications for patients with rare JAK1 PID and, more broadly, inform development of biomarker and targeted therapies for urothelial carcinoma.

Keywords: JAK1 deficiency, Bladder cancer, IFN gamma signalling, Immunodeficiency - primary, Urothelium

Received: 08 Feb 2019; Accepted: 15 Aug 2019.

Copyright: © 2019 Daza Cajigal, pearson, Hinley, Stahlschmidt, Thrasher, Mishra, Southgate and Burns. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Siobhan O. Burns, University College London, London, WC1E 6BT, England, United Kingdom, siobhan.burns@ucl.ac.uk