Morten Orebo Holmström
Reversion of local immune suppression in pancreatic cancer
This project aims at identifying new targets for therapeutic cancer vaccination in patients with pancreatic cancer (PC). The immunosuppressive cytokines interleukin (IL)-10 and transforming growth factor-beta (TGFb) are upregulated in PC and inhibit tumor specific T cells (Figure 1).(1–5) Several other immunoregulatory mechanisms are targets of specific T cells.(6–11) We aim at identifying, if T cells specific to IL-10 and TGFb- derived epitopes can recognize and kill immunosuppressive cells, as this will revert the local immune suppression in PC (Figure 2). Additionally, we wish to elucidate differences in the transcriptome between tumor specific T cells isolated from healthy donors (HD) and patients with PC.
The project will use basic immune-cellular assays such as ELISPOT and flow cytometry for identification of immunogenic epitopes in IL-10 and TGFb. More advanced assays such as co-culture assays will be used to determine the ability of TGFb- and IL-10 specific T cells to target regulatory and immunosuppressive cells. Murine vaccination models using both orthotopic and non-orthotopic tumor models will be used to asses the ability of IL-10 and TGFb-directed vaccination to induce tumor regression and changes in the tumor microenvironment. T cells specific for KRAS-oncoprotein(12,13) will be isolated using tetramers, and single cell RNA sequencing(14,15) will reveal transcriptomic differences between HD and patient T cells.
The project will establish the preclinical rationale for anti-regulatory therapeutic cancer vaccination(16) in PC and thereby allow us to go directly into a phase I clinical vaccination trial testing the safety and efficacy of such vaccines. Thus, our project has the potential to establish anti-regulatory T cell vaccines as a new treatment modality in PC. Identification of dysregulated mechanisms in tumor specific T cells in PC will identify additional mechanisms that may be targeted in order to enhance the tumor specific T cell responses in PC.
Basic mentor: Professor Niels Ødum, Department of Immunology and Microbiology, University of Copenhagen