The impact of the liver microenvironment on the immune checkpoint regulator PD-L1 in liver metastasis of pancreatic cancer

With a 5-year survival rate of under 5 %, pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies. In the European Union, PDAC represents the 4th most common cause of cancer-related deaths. Lacking specific symptoms, PDAC is mostly diagnosed at a locally advanced or metastatic stage, with the liver representing the main site of metastases and hepatic myofibroblasts (HMF) playing a pivotal role in metastatic outgrowth. To date, the only curative treatment is an R0 resection of the primary tumor. Since PDAC patients with liver metastases have an even worse prognosis, it is important to better understand the mechanisms underlying metastatic progression in the liver and to identify effective treatment options. Treatment with immune checkpoint inhibitors, e.g., targeting programmed cell death-ligand 1(PD-L1) or its receptor programmed cell death protein-1 (PD-1), has improved the therapy of many cancers but so far failed in PDAC. However, whether and how PD-L1 expression impacts immune evasion, especially in liver metastases, is still poorly understood, as they are not routinely resected in PDAC patients. Therefore, this study aimed to gain further insights into the impact of the liver microenvironment, particularly of HMF, on PDAC cells and CD8+ T cells in the context of immune evasion, focusing on PD-L1.

Overall, the findings of this thesis indicate a spatial reorganization of HMF, CD8+ T cells, and PD-L1 expression during progression of PDAC liver metastases. Furthermore, HMF potently impair the effector phenotype of CD8+ T cells but the PD-L1/PD-1 axis apparently plays a minor role in this scenario, suggesting that immune evasion of PDAC liver metastases relies on other immunosuppressive mechanisms.



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