Dissecting the role of leukocyte in cystic fibrosis cancer: how dysfunctional CFTR affect anti-tumor immunity

In the recent years, progresses in therapies through multidisciplinary care, in particular with the introduction of modulators, lead to a substantial rise in median life expectancy in cystic fibrosis (CF). Growing number of CF patients now started to face with clinical needs associated with older age such as cancer, in particular in the gastrointestinal (GI) tract. Previous studies evidenced an increased incidence of colorectal cancer in people with CF, especially after an organ transplant, and a more challenging management as compared to the general population. Therefore, a better understanding of pathophysiological mechanisms of CF cancer is urgently required. The present proposal aimed to fill this gap by investigating the CF immune system in cancer. This is of paramount importance since therapies that stimulates anti-tumor immunity have revolutionized cancer care, suggesting that a proper activation of the immune system is beneficial to improve patient’s outcome. Therefore, a detailed characterization of how CF leukocyte counter cancer could open innovative therapeutic strategies for the management of CF GI tumors. To address this issue, we will use relevant pre-clinical in vivo mouse models of GI CF cancer to determine how each single immune cell in CF reacts to tumor progression. Importantly, we will also evaluate the contribution of CF immunity and inflammation in the context of current pharmacological strategies in CF (modulators) and in GI cancer (chemotherapies and immune checkpoint inhibitors). Completion of this project will give information that can help clinicians towards a better definition of clinical effects of anti-cancer approaches in CF, which remains problematic. Importantly, the dissection of CF anti-tumor immunity at a single-cell level will provide fundamental clues for the future development of CF-specific anti-cancer approaches, ideally for each CFTR class mutation.