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Picard, Felix Simon Ruben; Lutz, Veronika; Brichkina, Anna; Neuhaus, Felix; Ruckenbrod, Teresa; Hupfer, Anna; Raifer, Hartmann; Klein, Matthias; Bopp, Tobias; Pfefferle, Petra Ina; Savai, Rajkumar; Prinz, Immo; Waisman, Ari; Moos, Sonja; Chang, Hyun-Dong; Heinrich, Stefan; Bartsch, Detlef K; Buchholz, Malte; Singh, Shiv; Tu, Mengyu; Klein, Lukas; Bauer, Christian; Liefke, Robert; Burchert, Andreas; [...]

IL-17A-producing CD8+T cells promote PDAC via induction of inflammatory cancer-associated fibroblasts

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  • Medientyp: E-Artikel
  • Titel: IL-17A-producing CD8+T cells promote PDAC via induction of inflammatory cancer-associated fibroblasts
  • Beteiligte: Picard, Felix Simon Ruben; Lutz, Veronika; Brichkina, Anna; Neuhaus, Felix; Ruckenbrod, Teresa; Hupfer, Anna; Raifer, Hartmann; Klein, Matthias; Bopp, Tobias; Pfefferle, Petra Ina; Savai, Rajkumar; Prinz, Immo; Waisman, Ari; Moos, Sonja; Chang, Hyun-Dong; Heinrich, Stefan; Bartsch, Detlef K; Buchholz, Malte; Singh, Shiv; Tu, Mengyu; Klein, Lukas; Bauer, Christian; Liefke, Robert; Burchert, Andreas; [...]
  • Erschienen: BMJ, 2023
  • Erschienen in: Gut
  • Sprache: Englisch
  • DOI: 10.1136/gutjnl-2022-327855
  • ISSN: 1468-3288; 0017-5749
  • Schlagwörter: Gastroenterology
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:sec><jats:title>Objective</jats:title><jats:p>Pancreatic ductal adenocarcinoma (PDAC) is characterised by an abundant desmoplastic stroma composed of cancer-associated fibroblasts (CAF) and interspersed immune cells. A non-canonical CD8<jats:sup>+</jats:sup>T-cell subpopulation producing IL-17A (Tc17) promotes autoimmunity and has been identified in tumours. Here, we evaluated the Tc17 role in PDAC.</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>Infiltration of Tc17 cells in PDAC tissue was correlated with patient overall survival and tumour stage. Wild-type (WT) or<jats:italic>Il17ra<jats:sup>-/-</jats:sup></jats:italic>quiescent pancreatic stellate cells (qPSC) were exposed to conditional media obtained from Tc17 cells (Tc17-CM); moreover, co-culture of Tc17-CM-induced inflammatory (i)CAF (Tc17-iCAF) with tumour cells was performed. IL-17A/F-, IL-17RA-, RAG1-deficient and<jats:italic>Foxn1<jats:sup>nu/nu</jats:sup></jats:italic>mice were used to study the Tc17 role in subcutaneous and orthotopic PDAC mouse models.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Increased abundance of Tc17 cells highly correlated with reduced survival and advanced tumour stage in PDAC. Tc17-CM induced iCAF differentiation as assessed by the expression of iCAF-associated genes via synergism of IL-17A and TNF. Accordingly, IL-17RA controlled the responsiveness of qPSC to Tc17-CM. Pancreatic tumour cells co-cultured with Tc17-iCAF displayed enhanced proliferation and increased expression of genes implicated in proliferation, metabolism and protection from apoptosis. Tc17-iCAF accelerated growth of mouse and human tumours in<jats:italic>Rag1<jats:sup>-/-</jats:sup></jats:italic>and<jats:italic>Foxn1<jats:sup>nu/nu</jats:sup></jats:italic>mice, respectively. Finally,<jats:italic>Il17ra</jats:italic>-expressed by fibroblasts was required for Tc17-driven tumour growth in vivo.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>We identified Tc17 as a novel protumourigenic CD8<jats:sup>+</jats:sup>T-cell subtype in PDAC, which accelerated tumour growth via IL-17RA-dependent stroma modification. We described a crosstalk between three cell types, Tc17, fibroblasts and tumour cells, promoting PDAC progression, which resulted in poor prognosis for patients.</jats:p></jats:sec>