Daza-Cajigal, VanessaAlbuquerque, Adriana SPearson, JoannaHinley, JenniferMason, Andrew SStahlschmidt, JensThrasher, Adrian JMishra, VibhashSouthgate, JenniferBurns, Siobhan O2024-09-102024-09-102019-09-10Daza-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;10:2065.1664-3224http://hdl.handle.net/20.500.13003/15020https://hdl.handle.net/20.500.12105/22717Inherited 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.enghttp://creativecommons.org/licenses/by/4.0/Bladder cancerIFN gamma signalingImmunodeficiencyJAK1UrotheliumUrinary Bladder NeoplasmsCytotoxicity, ImmunologicEpithelial CellsTelomeraseHumansCell Line, TumorDisease SusceptibilityLymphocytesBiomarkersInterferon-gammaImmunohistochemistrySTAT1 Transcription FactorMucous MembraneRNA, MessengerJanus Kinase 1Gene Expression Regulation, Neoplasticresearch articleAttribution 4.0 International3155202610206510.3389/fimmu.2019.02065Frontiers in Immunologyopen accessLínea Celular TumoralRegulación Neoplásica de la Expresión GénicaBiomarcadoresMembrana MucosaInmunohistoquímicaSusceptibilidad a EnfermedadesInterferón gammaLinfocitosHumanosJanus Quinasa 1Células EpitelialesTelomerasaCitotoxicidad InmunológicaARN MensajeroFactor de Transcripción STAT1Neoplasias de la Vejiga Urinaria2-s2.0-85072623380484955000001L629462701