Colorectal cancer (CRC) is the second most common cancer in women and third in men, and, overall, the fourth cause of tumor death world-wide. The chronic inflammation in patients with inflammatory bowel disease (IBD) represents one of the highest risk factors for CRC development. Thus, identification of novel cellular and molecular druggable targets able to restore the physiological balance of pro-inflammatory molecules is a pressing unmet need.
Natural killer (NK) cells and innate lymphoid cells (ILCs) are specialized cytokine producer cells which patrol environmental interfaces to defend against infections and protect barrier integrity. These cells also participate in regulating gut inflammation, playing both protective and pathogenic functions during colitis-associated cancer. However, most of the molecular mechanisms responsible for the promotion of inflammation and cancer remain to be elucidated, yet.
Members of the Signal Transducer and Activator of Transcription (STAT) family are important mediators for signaling events downstream of many cytokine receptors. Due to the relevance of JAK/STAT-signaling in both IBD and CRC, this pathway is an attractive therapeutic target. We have previously described a broad expression of STAT4 in intestinal ILCs expressing natural cytotoxicity triggering receptors (NCRs) and unraveled non-redundant roles of this transcription factor in NK and ILCs. Building upon these findings, we believe that by targeting STAT4 in ILCs we can achieve modulation of the inflammatory microenvironment during intestinal inflammation and cancer.
Overall, this research plan aims i) to establish the impact of the conditional deletion of STAT4 in NCR+ ILCs in the pathogenesis of CRC; ii) to identify STAT4-dependent effector programs in mouse ILCs, relevant for generation of novel strategies for prevention of colitis-induced CRC.
The proposed research plan is based on a multidisciplinary approach that will combine expertise in immunology, molecular and cellular biology, flow cytometry, mouse models and next-generation sequencing approaches. The research network has been built to combine the complementary expertise of immunologists with a strong background in the study of the role of NK and ILCs in health and disease to optimize the research plan and costs. The activities will be coordinated to exploit the knowledge, facilities and infrastructures available to each member of this unit. Additionally, the operational objectives are tightly linked and will be carried out in large part through a joint effort of the different principal investigators of the unit. Several factors lay the groundwork for successfully carry out the proposal, including the expertise in the field of NK cells and ILCs of the whole unit; the large amount of genome-wide data I have generated as foundation of my group; the network of outstanding collaborators in Sapienza University and abroad, who have already provided support on the establishment of my group; availability of mouse models of CRC.
Colorectal cancer counts more than 1 million new cases and more than 700.000 deaths each year. Although progress has been made to understand the pathogenesis of this disease, the molecular and cellular mechanisms responsible for the development of CRC have not been fully elucidated. The chronic inflammation associated with IBD is a risk factor, and, at the same time, the features of the immune cells infiltrating the tumor represent an important prognostic factor for CRC patients. In this context, our aim is to identify novel cellular and molecular pathways involved in regulation of the inflammatory response before development of cancer. Due to the relevance of STAT-signaling in both IBD and CRC and the landmark feature of ILCs to produce a vast repertoire of cytokines, and in a large quantity, we propose that understanding how STAT4 regulates ILC functions in the context of chronic inflammation and cancer will provide new paths to design preventive strategies for CRC.
Mouse models of intestinal inflammation have revealed both unique and redundant roles for ILCs, while their role in cancer is still poorly investigated. How these cells contribute to IBD and CRC in humans is still under debate and it represents a hot topic in the field of cancer immunology. Despite the possible redundant functions in humans, at steady state, it is undoubtedly clear that ILCs are potent and rapid cytokine producers. Here we propose that a better understanding on how ILC responses are regulated will provide a useful tool for the treatment of these diseases. The proposal relies on unique tools available to this unit, indeed, we have generated a novel mouse model allowing targeted deletion of Stat4 gene in NCR+ ILCs. This model will give us the golden opportunity to weigh the importance of the innate type 1 cytokine response in the contest of intestinal inflammation and cancer.
Understanding the role of ILCs and the molecular pathways associated with CRC has profound implications in Public Health at several levels. First, this proposal has a huge impact for both IBD and CRC patients. Indeed, we will identify pro-inflammatory modules which will be targeted to limit intestinal inflammation as well as to design preventive treatment of colitis-associated CRC. Second, the transcriptomic data we plan to generate in this proposal will have the potential to reveal new biological pathways and new players involved in the pathogenesis of CRC. Targeting these molecules by using available drugs or by synthesis of new small molecules will pave the way for novel therapeutic strategies. Finally, correlations between ILC phenotype/functions and cancer progression will improve the prognostic power of the Immunoscore, recently proposed for CRC.
We anticipate that our program of work will provide the scientific framework for the future design of preventive strategies for colitis-associated CRC by targeting pathogenic ILC programs driven by STAT4. Moreover, the data generated and the novel mice and reagents created will be a great resource that we will make freely available to the wider research community.