Characterization of trefoil factor-3 as a novel chemokine - evaluation of its function in immune cell differentiation and infiltration of prostate carcinoma

• Applicant: Privatdozent Dr. Michael Nowak
• Subject Area: Pathology ; Immunology
• Term: from 2015 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 281374545

Prostate cancer (PCa) is the second most diagnosed type of cancer among men worldwide. A mixture of myeloid and lymphoid immune cells infiltrates prostate tumors and other tumor entities. Among these populations, tumor-associated macrophages (TAM) and natural killer T (NKT) cells aggregate in tumors. The majority of NKT cells, termed type-I NKT cells, are activated by lipid-CD1d complexes and play an protective role in tumor biology. Tumor-derived products and other tumor-infiltrating cells impair the activation and function of NKT cells. TAMs are the main CD1d-expressing cell type in tumors and exhibit tumor-growth and metastases-promoting effects. The presence of TAMs in the infiltrates of some tumor entities has been linked with poor prognosis, whereas its prognostic value in PCa is not clear. TAMs differentiate from monocytes expressing several chemokine receptors and are attracted into the tumor microenvironment by tumor-derived chemokines.Trefoil factor-3 (TFF3) is a small protein (17 kDa) secreted from epithelial cells and frequently overexpressed in prostate carcinoma and other carcinomas. Although its role in epithelial wound healing and maintenance of epithelial integrity is well described, the function of TFF3 in tumor biology, its receptor and regulation remain unclear. Our unpublished data show that TFF3 attracts human monocytes mediated by the chemokine receptor CXCR4, thus clearly defines TFF3 as novel chemokine. In addition to its function as chemokine TFF3 regulates the differentiation of monocytes/macrophages towards a phenotype reminiscent of TAM/M2-macrophages.Aim of this project is to characterize the role of TFF3 and its receptor CXCR4 in the infiltration and function of immune cells in prostate cancer. Using the immune-competent prostate tumor mouse model TRAMP and in vitro systems we will address the impact of TFF3 and its receptor CXCR4 on macrophage differentiation and the subsequent stimulatory capacity to T and NKT cells. Using a clinically well-characterized large cohort of prostate cancer patients we will address the clinically relevant question whether TFF3 expression in human prostate tumors correlates with the infiltration of TAM and clinically relevant endpoints.In conclusion, results of this project will significantly enhance our understanding of tumor-mediated immune deviation in PCa. Together with answers about the role of TFF3 in macrophage differentiation and control of NKT cells, this study will support approaches to control immune- inhibitory and tumor-promoting effects of PCa-homing immune cells.

• DFG Programme: Research Grants