Journal Article

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

Liefke, Robert, Brichkina, Anna, Savai, Rajkumar, Heinrich, Stefan, Burchert, Andreas, Waisman, Ari, Gaida, Matthias, Huber, Magdalena, Bopp, Tobias, Klein, Matthias, Bartsch, Detlef K, Ruckenbrod, Teresa, Gress, Thomas M, Picard, Felix Simon Ruben, Prinz, Immo, Tu, Mengyu, Singh, Shiv, Neuhaus, Felix, Buchholz, Malte, Bauer, Christian, Mayer, Philipp, Moos, Sonja, Chang, Hyun-Dong, Raifer, Hartmann, Lauth, Matthias, Klein, Lukas, Hupfer, Anna, Lutz, Veronika, Chung, Ho-Ryun, Pfefferle, Petra Ina

2023

Overview

ObjectivePancreatic 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.DesignInfiltration 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.ResultsIncreased 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.ConclusionsWe 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.

• Publisher: BMJ Publishing Group Ltd and British Society of Gastroenterology,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Adenocarcinoma / Animal models / Apoptosis / Autoimmunity / cancer immunobiology / Cancer-Associated Fibroblasts - metabolism / Carcinoma, Pancreatic Ductal - pathology / CD8 antigen / CD8-Positive T-Lymphocytes / Cell culture / Cell proliferation / Cells / cytokines / Cytotoxicity / Fibroblasts / Gene expression / Homeodomain Proteins / Humans / Immune response / Inflammation / inflammatory mechanisms / Interleukin-17 - metabolism / Lymphatic system / Lymphocytes / Lymphocytes T / Medical prognosis / Metabolism / Metastases / Metastasis / Pancreas / Pancreatic cancer / Pancreatic Neoplasms / Pancreatic Neoplasms - pathology / RAG1 protein / Regression analysis / Signal transduction / Smooth muscle / Stellate cells / Stroma / Tumors