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oai:repisalud.isciii.es:20.500.12105/227172024-11-29T07:44:42Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16967

00925njm 22002777a 4500 dc Daza-Cajigal, Vanessa author Albuquerque, Adriana S author Pearson, Joanna author Hinley, Jennifer author Mason, Andrew S author Stahlschmidt, Jens author Thrasher, Adrian J author Mishra, Vibhash author Southgate, Jennifer author Burns, Siobhan O author 2019-09-10 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 (IFN gamma), 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 IFN gamma 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 IFN gamma stimulation and were resistant to IFN gamma-induced apoptosis and lymphocyte-mediated killing. In addition, we identify a previously unknown role for IFNy 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. Daza-Cajigal V, Albuquerque AS, Pearson J, Hinley J, Mason AS, Stahlschmidt J, et al. Loss of Janus Associated Kinase 1 Alters Urothelial Cell Function and Facilitates the Development of Bladder Cancer. Front Immunol. 2019 Sep 10;10:2065. 10.3389/fimmu.2019.02065 1664-3224 Frontiers in Immunology http://hdl.handle.net/20.500.13003/15020 31552026 L629462701 2-s2.0-85072623380 https://hdl.handle.net/20.500.12105/22717 484955000001 Bladder cancer IFN gamma signaling Immunodeficiency JAK1 Urothelium Loss of Janus Associated Kinase 1 Alters Urothelial Cell Function and Facilitates the Development of Bladder Cancer