T lymphocytes in pancreatic cancer: Evaluation of the role of alternative p38 pathway in an in vivo model

• Applicant: Professor Dr. Matthias Gaida
• Subject Area: Pathology
• Term: from 2012 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 214635648

Human malignancies are influenced by the cross-talk between tumor cells and their microenvironment, in particular by the inflammatory milieu and tumor-infiltrating lymphocytes (TIL). A key question in tumor-immunology is, why human malignancies progress in spite of the presence of a significant infiltration of immune cells. The focus of my work and this research proposal is to elucidate the biologic functions of TIL in the model of pancreatic cancer (PDAC). T cells are the predominant infiltrating inflammatory cells in PDAC. Nevertheless, whether TIL have anti- or protumorigenic potential is controversially discussed. In my previous work, I could show that PDAC cells interact with the immune system via various cytokines. Furthermore, T lymphocytes recognize MHC class II expressing PDAC cells, which leads to T cell proliferation. TIL are a major source of cytokines resulting in biological effects like cytotoxicity, cell growth, migration or apoptosis. Intracellular signaling pathways that lead to the production of many key cytokines are centrally regulated by the MAP kinase p38. In T cells, p38 is regulated in a unique manner by an alternative T cell receptor-dependent pathway. The aim of my project is to evaluate the role of this alternative p38 pathway in T cell mediated cytokine response and antitumor immune reaction towards PDAC. The project will be tackled taking advantage of the leading expertise of Jonathan D. Ashwell (NCI, Bethesda, MD, USA). He has developed unique mouse models in which the alternative p38 pathway is either functionally silenced (p38¿¿Y323F mouse) or permanently activated (Gadd45¿ knock out mouse). With these models, I will specifically evaluate whether and how silencing or over-activation of the alternative p38 pathway, regulate the interaction of T cells with PDAC, in particular the direct cytotoxic effects of cytotoxic and the role of Th cells. The final vision is to provide a basis for a novel immunotherapeutic approach against PDAC.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Dr. Jonathan Ashwell