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