Insights into the role of hepatic stromal cells and the immune checkpoint protein PD-L1 in liver metastases of pancreatic cancer
PDAC is the 7th leading cause of cancer deaths with a 9% 5-year survival, largely due to late diagnosis. The liver is the primary metastatic site, yet how the hepatic microenvironment influences disseminated pancreatic ductal epithelial cells (PDEC) remains unclear. While hepatic stellate cells (HSC) dominate physiological liver contexts, hepatic myofibroblasts (HMF) prevail under inflammation. Despite success in other cancers, PD-1/PD-L1 therapies show limited efficacy in PDAC, necessitating a better understanding of immune evasion. IHC analysis of human liver metastases revealed profound remodeling during progression. Large metastases (>1500µm) exhibited higher HMF abundance (αSMA) and proliferation (Ki67) than small lesions (≤1500µm). In small metastases, CD8+ T cells were evenly distributed, and PD-L1 was absent or central. Conversely, large metastases showed T-cell exclusion to the invasion front, where PD-L1 expression was highest. In vitro, HSCs suppressed PDEC growth by inducing senescence, while HMFs stimulated proliferation. Blockade of IL-8 or VEGF affected growth but had no impact on PD-L1 expression. Furthermore, neither the presence of HSCs/HMFs nor cytokine blockade influenced the cytotoxic activity of CD8+ T cells against PDECs. In conclusion, PDAC liver metastasis involves a spatial reorganization of HMFs, CD8+ T cells, and PD-L1. The hepatic microenvironment significantly dictates growth patterns: HSCs (physiological/small lesions) suppress growth, whereas HMFs (inflammatory/large lesions) stimulate it. However, these stromal cells do not appear to be the primary modulators of PD-L1 on PDECs, indicating that tumor-cell PD-L1 is not the main factor driving immune evasion in PDAC liver metastasis.
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