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Picard, Felix Simon Ruben
[VerfasserIn];
Lutz, Veronika
[VerfasserIn];
Brichkina, Anna
[VerfasserIn];
Neuhaus, Felix
[VerfasserIn];
Ruckenbrod, Teresa
[VerfasserIn];
Hupfer, Anna
[VerfasserIn];
Raifer, Hartmann
[VerfasserIn];
Klein, Matthias
[VerfasserIn];
Bopp, Tobias
[VerfasserIn];
Pfefferle, Petra Ina
[VerfasserIn];
Savai, Rajkumar
[VerfasserIn];
Prinz, Immo
[VerfasserIn];
Waisman, Ari
[VerfasserIn];
Moos, Sonja
[VerfasserIn];
Chang, Hyun-Dong
[VerfasserIn];
Heinrich, Stefan
[VerfasserIn];
Bartsch, Detlef K.
[VerfasserIn];
Buchholz, Malte
[VerfasserIn];
Singh, Shiv
[VerfasserIn];
Tu, Mengyu
[VerfasserIn];
Klein, Lukas
[VerfasserIn];
Bauer, Christian
[VerfasserIn];
Liefke, Robert
[VerfasserIn];
Burchert, Andreas
[VerfasserIn];
[...]
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 [VerfasserIn]; Lutz, Veronika [VerfasserIn]; Brichkina, Anna [VerfasserIn]; Neuhaus, Felix [VerfasserIn]; Ruckenbrod, Teresa [VerfasserIn]; Hupfer, Anna [VerfasserIn]; Raifer, Hartmann [VerfasserIn]; Klein, Matthias [VerfasserIn]; Bopp, Tobias [VerfasserIn]; Pfefferle, Petra Ina [VerfasserIn]; Savai, Rajkumar [VerfasserIn]; Prinz, Immo [VerfasserIn]; Waisman, Ari [VerfasserIn]; Moos, Sonja [VerfasserIn]; Chang, Hyun-Dong [VerfasserIn]; Heinrich, Stefan [VerfasserIn]; Bartsch, Detlef K. [VerfasserIn]; Buchholz, Malte [VerfasserIn]; Singh, Shiv [VerfasserIn]; Tu, Mengyu [VerfasserIn]; Klein, Lukas [VerfasserIn]; Bauer, Christian [VerfasserIn]; Liefke, Robert [VerfasserIn]; Burchert, Andreas [VerfasserIn]; Chung, Ho-Ryun [VerfasserIn]; Mayer, Philipp [VerfasserIn]; Gress, Thomas M. [VerfasserIn]; Lauth, Matthias [VerfasserIn]; Gaida, Matthias [VerfasserIn]; Huber, Magdalena [VerfasserIn]
- Erschienen: 9 February 2023
- Erschienen in: Gut ; 72(2023), 8, Seite 1510-1522
- Sprache: Englisch
- DOI: 10.1136/gutjnl-2022-327855
- ISSN: 1468-3288
- Identifikator:
- Schlagwörter: cancer immunobiology ; cytokines ; immune response ; inflammatory mechanisms ; pancreatic cancer
- Entstehung:
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Anmerkungen:
Im Titel ist das Pluszeichen hochgestellt
- Beschreibung: Objective 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+ T-cell subpopulation producing IL-17A (Tc17) promotes autoimmunity and has been identified in tumours. Here, we evaluated the Tc17 role in PDAC. - Design Infiltration of Tc17 cells in PDAC tissue was correlated with patient overall survival and tumour stage. Wild-type (WT) or Il17ra-/- 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 Foxn1nu/nu mice were used to study the Tc17 role in subcutaneous and orthotopic PDAC mouse models. - Results 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 Rag1-/- and Foxn1nu/nu mice, respectively. Finally, Il17ra-expressed by fibroblasts was required for Tc17-driven tumour growth in vivo. - Conclusions We identified Tc17 as a novel protumourigenic CD8+ 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.
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