Molecular mechanisms of immune evasion in colorectal carcinoma.

• Applicant: Privatdozentin Dr. Nathalie Britzen-Laurent
• Subject Area: General and Visceral Surgery ; Gastroenterology ; Pathology ; Cell Biology
• Term: from 2016 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 292410854

The infiltration of T helper 1 (Th1) T-cells and the expression of Interferon (IFN)-gamma-induced genes have been associated with an improved clinical outcome of patients with colorectal carcinoma (CRC). However, the mechanisms by which tumors can circumvent this immune reaction have not been yet fully characterized. Our previous data suggested that CRC tumor cells are able to become resistant to IFN-gamma, both in vitro and in situ in tumors. We found that CRC tumor cells are able to down-regulate IFN-induced genes and to resist the anti-proliferative and pro-apoptotic effects of IFN-gamma. The present project aims to determine the molecular mechanisms and the clinical significance of the acquired resistance to IFN-gamma in CRC cells. Preliminary experiments indicated that the down-regulation of the IFN-gamma receptor and the up-regulation of interleukin 10 (IL-10) and IL-10 receptor might be responsible for the loss of responsiveness to IFN-gamma in CRC cells. In the present project we aim to investigate whether the down-regulation of the expression of the IFN-gamma receptor in CRC tumor cells is sufficient to induce resistance to the anti-tumorigenic effects of IFN-gamma. In addition, we will analyze the influence of the specific deletion of IFN-gamma receptor in mouse colon epithelial cells on the development of colon tumor using different in vivo models. Finally, we want to assess the role and the clinical significance of the IL-10 pathway in the resistance of CRC cells to IFN-gamma. The ultimate goal of the present project is to prove the existence of a specific tumor evasion mechanism from the IFN-gamma-dominated immune response in CRC. This project may have important repercussions for prognosis and patients recruitment for immune-based therapy in CRC.

• DFG Programme: Research Grants