Primary Immunodeficiencies (PID) are inherited disorders associated with increased risk of infections, autoimmunity and malignancy. The later may be related to impaired antitumor immune responses or a direct role of germline mutations in tumorigenesis. We recently identified germline hypomorphic mutations in Janus Associated Kinase 1 (JAK1) causing primary immunodeficiency, characterised by mycobacterial infections and early onset fatal bladder carcinoma. JAK1 is required for immune cell signalling in response to different cytokines including interferons (IFNs). Somatic mutations in JAK1 have been associated with several cancer cell types and anti-tumour immune evasion, but pathogenic mechanisms remain largely unexplored.
Considering that our patient was diagnosed with an uncommon high grade metastatic bladder carcinoma at an early age, we investigated the role of partial JAK1 deficiency in tumour immune evasion, using aurothelial cell model generated with lentiviral vectors expressing short hairpin RNA (shRNA).
Here we demonstrate that JAK1 is required for the intrinsic IFNγ response of urothelial cells impacting on immunogenicity and cell survival. Specifically, urothelial cells with reduced JAK1-function showed lower cell surface levels of major histocompatibility complex class 2 (MHC II), intercellular adhesion molecule-1 (ICAM-1) and programmed death-ligand-1 (PD-L1) after IFNγ stimulation and were resistant to apoptosis and lymphocyte-mediated killing. In addition, we identified a previously unknown role for IFNγ signalling in modulating urothelial cell differentiation.
Together, our findings support a role for JAK1 in tumorigenesis and immune surveillance. Our results have implications for patients with PID and the development of biomarkers and targeted therapies for urothelial carcinoma.