Background and Aims

Many primary immunodeficiencies (PIDs) start in childhood and are life-threatening. Treatment includes haematopoietic stem cell transplant (HSCT). Due to improved techniques, more transplants are undertaken and patients are living longer. However, long-term complications can significantly affect future health and quality of life.

Previous research has focused on short-term medical outcomes and little is known about health or psychosocial outcomes in adulthood. This project is the largest and most comprehensive evaluation of long-term physical, social and psychological outcomes for adults who underwent HSCT for PID during childhood.

Methods

83 adult patients, who underwent HSCT for PID at Great Ormond Street Hospital during childhood, and at least five years previously, were recruited. Questionnaires and practical tasks assessed their current functioning and circumstances. Information was also gathered from medical notes. Data was compared with population norms and a control group of participant-nominated siblings or friends.

Results

The majority of participants reported satisfaction with their overall wellbeing. However, patients reported significantly poorer physical health-related quality of life than peers, and decreased cognitive and social functioning in some domains. These and other psychosocial, physical and cost-effectiveness outcomes will be presented.

Conclusions

Implications and suggestions for future research and service development will be discussed.

This abstract presents independent research funded by the NIHR under its Research for Patient Benefit Programme (Grant Reference Number PB-PG-0215-36145). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.

Background and Aims

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.

Methods

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).

Results

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.

Conclusions

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.