From inflammatory bowel disease to colon cancer: involvement of innate lymphocytes in early pathogenic mechanisms

Inflammatory bowel disease (IBD) remains an urgent global health problem with about 6 million individuals affected worldwide. A widely variable percentage of patients with IBD progresses to chronic inflammation and around 20% - 30% develop colon cancer within their lifetime. The health economic burden and permanent work disability in IBD are very high in Europe with a total yearly direct healthcare cost of 4.6-5.6 billion Euros. The economic impact is even higher since IBD can affect patients at an early age. Although several risk factors for the development of IBD have been identified including genetic factors, smoking, dietary factors and microbial pathogens, a full understanding of IBD pathogenesis is unclear. Dysregulation of immune response in the intestine plays a critical role in the pathogenesis of IBD and involves a wide range of cytokines leading to the development of several immune-targeted treatments, such as biologic agents directed against the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). However, a significant number of patients with IBD are refractory to anti-TNF-alpha therapy, therefore indicating that a shift towards other inflammatory pathways may occur. Besides T helper (Th) 1 and Th2 cell immune responses, other subsets of T cells, namely Th17/Th22 have been associated with disease progression. Although the adaptive immune response has classically been considered to play a major role in the pathogenesis of IBD, recent advances in immunology have clarified that the innate immune response plays an equally important, or perhaps even primary, role in initiating and maintaining inflammation in IBD. In particular, since intestinal inflammation and altered mucosal healing are essential features in the pathogenesis of chronic IBD that evolves to colon cancer, the present project will focus on the role of innate lymphocytes more strictly associated to mucosal tissues, such as the emerging family of innate lymphoid cells (ILCs) and gamma-delta T cells.
The project will be carried out through an interdisciplinary research platform combining integrated approaches with the aim to evaluate the dynamic change of different populations of innate lymphocytes as well as their causative role in the transition from IBD to CRC. In addition, the multiple rounds of damage and repair occurring in chronic IBD, often result in an accumulation of stem cells that, in the regenerative effort, can eventually promote tumor initiation. Thus, special attention will be given to the mechanisms of cross-talk between the innate lymphocyte population and intestinal stem cells, investigating the signals required for their self-renewal vs differentiation capability. Results from the present proposal could generate new knowledge about the early pathogenic mechanisms driving IBD-associated cancer. In particular, identification of innate immune pathways involved in transition to chronic IBD and CRC could be exploited to define a biomarker signature that may be useful for the development of new diagnostics, the identification of IBD patients with the highest risk to develop CRC and even planning novel and more effective therapies for the treatment of IBD.