Loss of Janus Associated Kinase1 alters urothelial cell functionand facilitates the development of bladder cancer

Vanessa Daza-Cajigal; Adriana Albuquerque; Joanna Frances Pearson; Jennifer Susan Hinley; Andrew Stephen Mason; Jens Stahlschmidt; Adrian J. Thrasher; Vibash Mishra; Jennifer Southgate; Siobhan O. Burns

doi:10.3389/fimmu.2019.02065

Loss of Janus Associated Kinase1 alters urothelial cell functionand facilitates the development of bladder cancer

Vanessa Daza-Cajigal, Adriana Albuquerque, Joanna Frances Pearson, Jennifer Susan Hinley, Andrew Stephen Mason, Jens Stahlschmidt, Adrian J. Thrasher, Vibash Mishra, Jennifer Southgate, Siobhan O. Burns

Research output: Contribution to journal › Article › peer-review

Abstract

Inherited Primary Immunodeficiency (PID) disorders are associated with increased risk ofmalignancy that may relate to impaired antitumor immune responses or a direct role for PIDgermline mutations in tumorigenesis. We recently identified germline loss of function mutations inJanus Associated Kinase 1 (JAK1) causing primary immunodeficiency characterised by infectionsand 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 associatedwith several non-hematopoietic and hematopoietic cancer cell types but pathogenic mechanismsremain largely unexplored. Here we demonstrate that JAK1 is required for the intrinsic IFNγresponse of urothelial cells impacting immunogenicity and cell survival. Specifically, JAK1-deficient urothelial cells showed reduced surface expression of major histocompatibility complexclass 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 lymphocytemediatedkilling. In addition, we identify a previously unknown role for IFNγ signalling inmodulating urothelial differentiation. Together, our findings support a role for urothelial cell JAK1in immune surveillance and development of bladder cancer. Our results have implications forpatients with rare JAK1 PID and, more broadly, inform development of biomarker and targetedtherapies for urothelial carcinoma.

Original language	English
Journal	Frontiers in immunology
DOIs	https://doi.org/10.3389/fimmu.2019.02065
Publication status	Published - 10 Sept 2019

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10.3389/fimmu.2019.02065Licence: CC BY

Southgate - 453306_Burns_Manuscript (accepted)Accepted author manuscript, 652 KB

Cite this

@article{e85ec14c91c44f579e3dfe502a986a79,

title = "Loss of Janus Associated Kinase1 alters urothelial cell functionand facilitates the development of bladder cancer",

abstract = "Inherited Primary Immunodeficiency (PID) disorders are associated with increased risk ofmalignancy that may relate to impaired antitumor immune responses or a direct role for PIDgermline mutations in tumorigenesis. We recently identified germline loss of function mutations inJanus Associated Kinase 1 (JAK1) causing primary immunodeficiency characterised by infectionsand 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 associatedwith several non-hematopoietic and hematopoietic cancer cell types but pathogenic mechanismsremain largely unexplored. Here we demonstrate that JAK1 is required for the intrinsic IFNγresponse of urothelial cells impacting immunogenicity and cell survival. Specifically, JAK1-deficient urothelial cells showed reduced surface expression of major histocompatibility complexclass 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 lymphocytemediatedkilling. In addition, we identify a previously unknown role for IFNγ signalling inmodulating urothelial differentiation. Together, our findings support a role for urothelial cell JAK1in immune surveillance and development of bladder cancer. Our results have implications forpatients with rare JAK1 PID and, more broadly, inform development of biomarker and targetedtherapies for urothelial carcinoma.",

author = "Vanessa Daza-Cajigal and Adriana Albuquerque and Pearson, {Joanna Frances} and Hinley, {Jennifer Susan} and Mason, {Andrew Stephen} and Jens Stahlschmidt and Thrasher, {Adrian J.} and Vibash Mishra and Jennifer Southgate and Burns, {Siobhan O.}",

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doi = "10.3389/fimmu.2019.02065",

language = "English",

journal = "Frontiers in immunology",

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T1 - Loss of Janus Associated Kinase1 alters urothelial cell functionand facilitates the development of bladder cancer

AU - Daza-Cajigal, Vanessa

AU - Albuquerque, Adriana

AU - Pearson, Joanna Frances

AU - Hinley, Jennifer Susan

AU - Mason, Andrew Stephen

AU - Stahlschmidt, Jens

AU - Thrasher, Adrian J.

AU - Mishra, Vibash

AU - Southgate, Jennifer

AU - Burns, Siobhan O.

PY - 2019/9/10

Y1 - 2019/9/10

N2 - Inherited Primary Immunodeficiency (PID) disorders are associated with increased risk ofmalignancy that may relate to impaired antitumor immune responses or a direct role for PIDgermline mutations in tumorigenesis. We recently identified germline loss of function mutations inJanus Associated Kinase 1 (JAK1) causing primary immunodeficiency characterised by infectionsand 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 associatedwith several non-hematopoietic and hematopoietic cancer cell types but pathogenic mechanismsremain largely unexplored. Here we demonstrate that JAK1 is required for the intrinsic IFNγresponse of urothelial cells impacting immunogenicity and cell survival. Specifically, JAK1-deficient urothelial cells showed reduced surface expression of major histocompatibility complexclass 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 lymphocytemediatedkilling. In addition, we identify a previously unknown role for IFNγ signalling inmodulating urothelial differentiation. Together, our findings support a role for urothelial cell JAK1in immune surveillance and development of bladder cancer. Our results have implications forpatients with rare JAK1 PID and, more broadly, inform development of biomarker and targetedtherapies for urothelial carcinoma.

AB - Inherited Primary Immunodeficiency (PID) disorders are associated with increased risk ofmalignancy that may relate to impaired antitumor immune responses or a direct role for PIDgermline mutations in tumorigenesis. We recently identified germline loss of function mutations inJanus Associated Kinase 1 (JAK1) causing primary immunodeficiency characterised by infectionsand 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 associatedwith several non-hematopoietic and hematopoietic cancer cell types but pathogenic mechanismsremain largely unexplored. Here we demonstrate that JAK1 is required for the intrinsic IFNγresponse of urothelial cells impacting immunogenicity and cell survival. Specifically, JAK1-deficient urothelial cells showed reduced surface expression of major histocompatibility complexclass 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 lymphocytemediatedkilling. In addition, we identify a previously unknown role for IFNγ signalling inmodulating urothelial differentiation. Together, our findings support a role for urothelial cell JAK1in immune surveillance and development of bladder cancer. Our results have implications forpatients with rare JAK1 PID and, more broadly, inform development of biomarker and targetedtherapies for urothelial carcinoma.

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DO - 10.3389/fimmu.2019.02065

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