Selective elimination of immunosuppressive cell populations and modulation of microenvironment for improvement of T cell infiltration of the pancreatic ductal adenocarcinoma

• Applicant: Dmitrij Ostroumov, Ph.D.
• Subject Area: Gastroenterology ; Immunology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 513557571

Specific antitumoral T cell responses play a key role in the suppression of cancer diseases. Understanding of immunoregulatory mechanisms and contribution of different cell populations in the tumor is fundamental for the development of efficacious immunotherapies. Our preliminary studies addressed the functional exhaustion of tumor-specific CD8 T cells, where the exploitation of co-inhibitory regulatory mechanisms by the tumor prevents an effective eradication of cancer cells. In this process we obtained comprehensive data on transcriptional changes in exhausted tumor-specific CD8 T cells and could subsequently verify the functional relevance of selected candidates. Moreover, we have developed diverse strategies and efficacious methods of therapeutic vaccination against cancer diseases. One substantial requirement for the elimination of cancer cells is the infiltration of malign tissue by cytotoxic T cells. Since various immunoregulatory mechanisms in the tumor microenvironment impede an effective T cell immunity, overcoming this local immunosuppression is crucial for the success of antitumoral T cell vaccines and immunotherapies. However, clinical data show that not all types of cancer are amenable to immunotherapy. Utilizing preclinical models we shall investigate therapeutic measures for effective treatment of cancer types that are, so far, resistant to immunotherapy. Among these is pancreatic ductal adenocarcinoma (PDAC) that is characterized by recruitment of different immunosuppressive cell populations in the tumor environment and resistance against immunotherapies. On this account we will selectively deplete diverse suppressive immune cells in order to abrogate the local immunosuppression. The goal here is the improvement of T cell infiltration into the tumor. Using expression control of selected candidate genes in our established mouse models is meant to abolish immunosuppression in the tumor, enabling cytotoxic CD8 T cells to enter the tumor. Because different cell populations are involved in the dynamic emergence of therapy resistance in PDAC comprehensive immunohistological and flow cytometric analyses will be performed, in order to identify synergistic therapies. The gained understanding of the involvement of diverse immune cell populations in the tumor environment bears meaning for translational research and could be significant for the improvement of the clinical situation in tumor patients. In this project combinations of immune checkpoint blockade will be evaluated that could also be efficacious for the treatment of metastasis.

• DFG Programme: Research Grants