The role of interleukin-25-producing T-helper-cells during colitis-associated and spontaneous colon tumorigenesis

• Applicant: Professor Dr. Stefan Fichtner-Feigl
• Subject Area: General and Visceral Surgery ; Gastroenterology ; Immunology
• Term: from 2014 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 259317850

Colorectal cancer is a common and malignant disease that includes various subtypes and their therapeutic options are still insufficient. Interleukin-25 is a cytokine of the interleukin-17 family and plays a central role in the intestinal immune homeostasis and defense against infection. In addition to intestinal epithelial cells, the known source of interleukin-25, we can now demonstrate the existence of interleukin-25-producing T helper cells in the intestine. Several indicators, including our own preliminary work suggest a pathological significance of this new line of T-cell differentiation in the development of colorectal carcinomas. The aim of the project is to highlight the importance of interleukin-25-producing T helper cells for intestinal tumorigenesis in detail. In the center of this proposal are in vivo experiments with well-established experimental models and the molecular analysis of intestinal tumorigenesis. This project is subject to the following hypotheses : 1) Th25 cells initiate IL-13+ NKT-cell-mediated murine ulcerative colitis and support colitis-associated tumor progression. The differentiation of IL-13+ NKT-cells is mainly induced by Th25 cells (not by IL-25-producing epithelial cells). 2) Tumor-infiltrating Th25 cells mediate an immunological tumor control via granzyme B and perforin and suppress the progression of spontaneous colon tumors. The project will answer the following questions: 1) Does the absence of interleukin-25-producing lymphocytes affect intestinal barrier function or bacterial translocation in the colon? 2) Is there a different distribution pattern of Th25 cells (in particular tumor-infiltrating Th25 cells) and can an alteration of granzyme B and perforin expression be detected during colitis-associated and spontaneous colon tumorigenesis? 3) Are Th25 cells necessary for the chronic oxazolone colitis in the AOM-oxazolone tumor model and are Th25 cells pro-tumorigenic or outweighs their cytotoxic activity against tumor cells? 4) Does secreted IL-25 mediate its effects mainly on immune cells via modification of the inflammatory response or directly on IL-17RB+ intestinal epithelial/tumor cells? 5 ) Is there a correlation of the infiltration by Th25 cells with the local inflammatory activity in human ulcerative colitis and with tumor stage of patients with sporadic colorectal cancer? Are there any molecular differences between Th25 cells isolated from human ulcerative colitis or sporadic colorectal cancer? The target of this project thus is to examine the role of interleukin-25-producing T helper cells in the formation and growth of colorectal cancer and explore potential opportunities for intervention in this immunological cascade.

• DFG Programme: Research Grants