Dottorato in INNOVATION IN IMMUNO-MEDIATED AND HEMATOLOGICAL DISORDERS

Titolo della tesi: Dissecting roles for NCR+ ILCs in colitis and colitis-induced colorectal cancer

Innate lymphoid cells (ILCs) comprise distinct lymphocytes, with Natural Killer (NK) cells being the founding member of the family. The role of ILCs in intestinal homeostasis and in protection against pathogens is now well established, however, recent findings are linking distinct ILC subsets to pathological conditions, including insurgence of autoimmune and inflammatory diseases, as well as to cancer progression. Given the preferential location of ILCs at mucosal interface as well as the importance of cytokine signalling for their activation, understanding how external cues are processed and converted into transcriptional reprogramming might provide the rationale for novel therapies against colitis and colorectal cancer. Thus, by using murine models and transcriptomic approaches, our study aims at investigating the role of STAT4 in enabling inflammatory modules in ILCs expressing the natural cytotoxicity receptor (NCR), NKp46. In particular, in the first part of our study, we revealed how NCR+ ILC3 in the small intestine lamina propria acquire type 1 features under the influence of STAT4. In the second part of our study, we explored how the ILC landscape of the large intestine lamina propria evolves during colitis and colorectal cancer, as well as we investigated the role of type 1 innate immunity and STAT4 in supporting inflammatory states in the large intestine. Taken together oud data provide evidence for the importance of STAT4 in driving a type 1 identity, as well as in unlocking pathogenic inflammatory modules in NCR+ ILCs.