000K utf8 1100 $c2023 1500 eng 2050 urn:nbn:de:gbv:8:3-2024-00042-3 2051 10.3389/fonc.2023.1160824 3000 Beckinger, Silje Victoria 3010 Aldag, Leon 3010 Daunke, Tina 3010 Heckl, Steffen 3010 Krüger, Sandra 3010 Rahn, Sascha 3010 Röcken, Christoph 3010 Schäfer, Heiner 3010 Sebens, Susanne 3010 Wesch, Daniela 4000 Hepatic myofibroblasts exert immunosuppressive effects independent of the immune checkpoint regulator PD-L1 in liver metastasis of pancreatic ductal adenocarcinoma$hFrontiers Media SA [Beckinger, Silje Victoria] 4030 $nFrontiers Media SA 4209 Results Immunohistochemical analysis of liver tissue sections of PDAC patients revealed that HMF represent an abundant stroma population in liver metastases, with clear differences in the spatial distribution in small (1500 µm) and large (> 1500 μm) metastases. In the latter, PD-L1 expression was mainly located at the invasion front or evenly distributed, while small metastases either lacked PD-L1 expression or showed mostly weak expression in the center. Double stainings revealed that PD-L1 is predominantly expressed by stromal cells, especially HMF. Small liver metastases with no or low PD-L1 expression comprised more CD8+ T cells in the tumor center, while large metastases exhibiting stronger PD-L1 expression comprised less CD8+ T cells being mostly located at the invasion front. HMF-enriched spheroid cocultures with different ratios of PDAC cells and HMF well mimicking conditions of hepatic metastases in situ. Here, HMF impaired the release of effector molecules by CD8+ T cells and the induction of PDAC cell death, an effect that was dependent on the amount of HMF but also of PDAC cells. ICI treatment led to elevated secretion of distinct CD8+ T cell effector molecules but did not increase PDAC cell death under either spheroid condition. Conclusion Our findings indicate a spatial reorganization of HMF, CD8+ T cells, and PD-L1 expression during progression of PDAC liver metastases. Furthermore, HMF potently impair the effector phenotype of CD8+ T cells but the PD-L1/PD-1 axis apparently plays a minor role in this scenario suggesting that immune evasion of PDAC liver metastases relies on other immunosuppressive mechanisms. 4950 https://doi.org/10.3389/fonc.2023.1160824$xR$3Volltext$534 4950 https://nbn-resolving.org/urn:nbn:de:gbv:8:3-2024-00042-3$xR$3Volltext$534 4961 https://macau.uni-kiel.de/receive/macau_mods_00004323 5051 610 5550 3D Coculture 5550 Hepatic Metastasis 5550 Immune Evasion 5550 Pancreatic cancer 5550 Programmed Death Ligand 1 5550 Tumor Microenvironment