The expression and role of the immune checkpoint regulator Programmed Cell Death Protein 1-Ligand 1 in the tumor-stroma interplay of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related death in Western countries. This high mortality is associated with the late stage of disease at diagnosis due to the lack of specific symptoms and poor specificity of tumor markers. Immune checkpoint inhibitors (ICI), e.g., targeting programmed cell death protein 1-ligand 1 (PD-L1) or its receptor PD-1, have markedly improved therapy of many cancers but so far failed in PDAC. Macrophages represent one of the most abundant immune cell populations within the tumor microenvironment (TME) of PDAC being able to either support or restrain tumor progression. To better understand treatment failure of PD-L1/PD-1 inhibitors in PDAC, this thesis examined PD-L1 expression in the context of a dynamic TME in PDAC with a particular focus on the impact of macrophages.

Immunohistochemical analyses revealed that PD-L1 is mainly expressed by stroma cells, including macrophages and not PDAC cells in primary PDAC tissues and corresponding liver metastases. Notably, a high local abundance of macrophages and strong PD-L1 staining were commonly found at invasion fronts of tumoral lesions between CD8+ T cells and tumor cells.

In a 3D spheroid model comprising PDAC cells and different ratios of in vitro differentiated primary M1- or M2-like macrophages, high PD-L1 expression was observed in macrophages. The effector phenotype of co-cultured CD8+ T cells was rather enhanced by PDAC macrophage spheroids. However, this was not associated with enhanced PDAC cell death. ICI treatment with either Durvalumab or Pembrolizumab alone or in combination with Gemcitabine hardly affected the effector phenotype of CD8+ T cells along with PDAC cell death.

Thus, despite strong PD-L1 expression in macrophages, ICI treatment did not result in an enhanced cytotoxic phenotype of CD8+ T cells, suggesting that PD-1/PD-L1 axis is not the main immunosuppressive mechanism in PDAC.


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