TGF-β mediated epigenetic control of anti-tumor natural killer cells in primary liver cancer

• Applicant: Dr. Gabriela Wiedemann
• Subject Area: Gastroenterology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 460245557

Natural killer (NK) cells are cytotoxic innate lymphoid cells defined by the capacity to rapidly target infected and malignant cells without prior sensitization. Thus, they have long been appreciated as a central player in the anti-tumoral immune response. However, cancers have found intricate ways of evading NK cell-mediated killing, and NK cells in advanced solid cancers are often scarce and functionally impaired. A central pathway of tumor induced immunosuppression is TGF-β signaling. Increased levels of TGF-β have been described in many solid tumors and the immunosuppressive effects of TGF-β signaling are versatile: apart from shaping the adaptive immune response, TGF-β has also been shown to impede NK cell functions, e.g. by down-regulation of activating receptors and inhibition of interferon (IFN)-γ production. However, the exact mechanisms by which TGF-β regulates NK cell responses have not been investigated. The aim of this project is to identify TGF-β target genes in NK cells and to delineate their role in tumor-associated NK cells. In her previous research projects, the applicant has gained expertise in the analysis of tumor-immune cell interactions and in the analysis of transcriptional and epigenetic cytokine networks in NK cells. The host institute can provide the technical equipment for the molecular analyses, state-of-the-art genetically engineered murine tumor models and tissue samples from cancer patients. First, we will conduct a genome-wide analysis of TGF-β transcriptional target genes and TGF-β induced epigenetic modifications in NK cells. Secondly, top target genes of TGF-β signaling in NK cells will be analyzed in murine models of cholangiocellular carcinoma (CCA) and hepatocellular carcinomas (HCC) over the course of tumor formation and progression. Finally, human CCA and HCC tissues will be analyzed for NK cell infiltration and expression of TGF-β target genes and their impact on the patients’ prognosis. The results of this project will provide invaluable new insights into how NK cell functions are shaped by the tumor microenvironment (TME) and will help to further develop NK cell-based immunotherapeutic approaches in cancer therapy.

• DFG Programme: Independent Junior Research Groups