Role of L1CAM in migration and effector function of regulatory T cells in pancreatic ductal adenocarcinoma and its potential for improved therapy

• Applicant: Professorin Dr. Susanne Sebens
• Subject Area: General and Visceral Surgery
• Term: from 2010 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 191998819

The promigratory molecule L1CAM (L1, CD171) is overexpressed in numerous highly malignant tumors being associated with poor prognosis for the patients. We already demonstrated an elevated L1CAM expression in pancreatic ductal adenocarcinoma (PDAC) and a role for L1CAM in cell migration and apoptosis resistance. Moreover, the presence of myofibroblasts leads to upregulation of L1CAM expression in a TGF-ß1 dependent manner already in pancreatic ductal epithelial cells (HPDE), a mechanism which still operates in TGF-ß1 responsive PDAC cells. In peripheral blood and tumor tissue of PDAC patients, the prevalence of regulatory T cells (Tregs) is elevated and can be associated with short survival. Until now, the mechanisms underlying enrichment of Tregs in the tumor as well as their direct pro-tumorigenic effects are poorly understood, in particular in the highly malignant PDAC. Thus, the project aims to investigate how the tumor microenvironment affects enrichment and effector function of Tregs with particular emphasis on L1CAM, and vice versa how Tregs contribute to the malignant transformation of PDAC. By using a Tie2-Cre; L1floxed mouse model the impact of L1CAM on tumor infiltration of Tregs and tumor progression will be analysed in vivo. Finally, the therapeutic targeting of L1CAM on tumor accumulation of Tregs and tumor progression will be validated in preclinical studies and the subsequent transfer of these results into the clinic is envisioned.

• DFG Programme: Research Grants
• Participating Person: Professor Dr. Heiner Schäfer