Programmed death ligand 1 (PD-L1) cell-intrinsic signaling in pancreatic cancer – Influence on tumor metabolism, microenvironment and disease progression

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Pancreatical ductal adenocarcinoma (PDAC) is one leading cause of cancer related deaths worldwide. In the last few years immune checkpoint targeting therapies were associated with therapeutic advances in several cancers. Especially targeting of the Programmed death 1/Programmed death ligand 1 (PD-1/PD-L1) axis seems to have a beneficial impact. PD-L1 is expressed in human pancreatic cancers and the tumor microenvironment (TME) and may be involved in tumor progression. Interaction of PD-L1 and T cell-bound PD-1 leads to exhaustion and dysfunction of cytotoxic T cells. In addition, recent data suggest that PD-L1 has a major influence on the metabolic imbalance between tumor cells and the TME. The aim of this proposal is to elucidate the key role of PD-L1 cell intrinsic signaling in PDAC cells regarding tumor metabolism and T cell response. Our hypothesis will be approached as follows: 1) PD-L1 modified PDAC cells will be generated using CRISPR technology. The altered phenotype of the generated cells will be assessed using a broad immunologic and metabolic panel of assays. Both, surface culture and organoid culture will be performed. 2) Modified cell lines from (1) will be orthotopically implanted into wildtype mice to mimic the human PDAC phenotype. The impact of PD-L1 alterations on tumor progression and the tumor micro environment will be monitored and compared. The focus will be put on positron-emission-tomography/ computed tomography (PET/CT) imaging, survival statistics and the immunologic and metabolic phenotypes of the murine model. There is an urgent need for new strategies for PDAC treatment and early diagnosis of the disease. This project will make a substantial contribution to the understanding of PD-1/PD-L1 intrinsic signaling in PDAC and potentially influence multimodal future treatment of this devastating disease.