Role of chemokines in T-cell chemo- and fugetaxis in pancreatic cancer

• Applicant: Professor Dr. Eduard Ryschich
• Subject Area: General and Visceral Surgery
• Term: from 2011 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 203471293

Intrastromal T cell trapping represents one of the major obstacles for effective immune response in human pancreatic cancer. Our previous studies showed that intratumoral collagen matrix misguides chemokine-directed T cell migration and that it forms a physical barrier for regular distribution of antitumoral T cells. However, collagen in stroma of pancreatic cancer is heterogeneously deposited, forming areas of different alignment and different density. Furthermore, tumor stroma contains macrophages which produce cytokines and can directly interact with migrating T cells. It allows to expand the above paradigm and to hypothesize that the chemokine-guided T cell migration in pancreatic cancer is a complex process which is influenced by the spatial organization and by the cellular microenvironment of tumor stroma. In context of the emerging role of cancer immunotherapy, the examination of this hypothesis has a very high translational relevance. It will help to understand and to predict the T cell immune response depending on individual spatial and cellular organisation of tumor stroma, It will also help to redirect immunotherapy and therapeutic interventions targeting tumor stroma. We proposed that the modulation of matrix organisation, but not the complete matrix depletion may provide an alternative clinical concept to improve results of immunotherapy in pancreatic cancer. The aim of the study is the detailed investigation of the role of extracellular matrix organisation and macrophages on matrix- and chemokine-guided T cell migration in pancreatic cancer. The work program will be dedicated to three important parts: (1) Influence of collagen organisation on contact guidance and chemokine-guided T cell migration; (2) Influence of different matrix compounds and macrophages on contact guidance and chemokine-guided migration of T cells; (3) Influence of stroma reengineering on T cell-mediated immune response in pancreatic cancer. The work program will be realized using studied on human pancreatic cancer tissue, adhesion and migration studies of activated and tumor-derived T cells and by evaluation of selected stroma-destructive strategies in tumor xenograft models.

• DFG Programme: Research Grants