Daza-Cajigal, V;
Albuquerque, AS;
Pearson, J;
Hinley, J;
Mason, AS;
Stahlschmidt, J;
Thrasher, AJ;
... Burns, SO; + view all
(2019)
Loss of Janus Associated Kinase 1 Alters Urothelial Cell Function and Facilitates the Development of Bladder Cancer.
Frontiers in Immunology
, 10
, Article 2065. 10.3389/fimmu.2019.02065.
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Abstract
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 characterized by infections and associated with early onset, fatal high-grade bladder carcinoma. Somatic mutations in JAK1, required for immune cell signaling 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 signaling 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.
| Type: | Article |
|---|---|
| Title: | Loss of Janus Associated Kinase 1 Alters Urothelial Cell Function and Facilitates the Development of Bladder Cancer |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3389/fimmu.2019.02065 |
| Publisher version: | https://doi.org/10.3389/fimmu.2019.02065 |
| Language: | English |
| Additional information: | Copyright © 2019 Daza-Cajigal, Albuquerque, Pearson, Hinley, Mason, 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. |
| Keywords: | bladder cancer, IFNγ signaling, immunodeficiency, JAK1, urothelium |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10082275 |
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