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

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

doi:10.1136/gutjnl-2022-327855

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

Gut. 2023 Aug;72(8):1510-1522. doi: 10.1136/gutjnl-2022-327855. Epub 2023 Feb 9.

Authors

Felix Simon Ruben Picard^#¹, Veronika Lutz^#¹, Anna Brichkina^#², Felix Neuhaus¹, Teresa Ruckenbrod¹, Anna Hupfer², Hartmann Raifer^{1

3}, Matthias Klein⁴, Tobias Bopp⁴, Petra Ina Pfefferle⁵, Rajkumar Savai^{6

7}, Immo Prinz⁸, Ari Waisman⁹, Sonja Moos⁹, Hyun-Dong Chang^{10

11}, Stefan Heinrich¹², Detlef K Bartsch¹³, Malte Buchholz², Shiv Singh¹⁴, Mengyu Tu¹⁴, Lukas Klein¹⁴, Christian Bauer², Robert Liefke¹⁵, Andreas Burchert¹⁶, Ho-Ryun Chung¹⁷, Philipp Mayer¹⁸, Thomas M Gress², Matthias Lauth², Matthias Gaida^{19

20

21}, Magdalena Huber²²

Affiliations

¹ Institute of Systems Immunology, Philipps-University Marburg, Marburg, Germany.
² Department of Gastroenterology, Endocrinology, Metabolism and Infection, Center for Tumor and Immunology (ZTI), Philipps-University Marburg, Marburg, Germany.
³ Core-Facility Flow Cytometry, Philipps-University Marburg, Marburg, Germany.
⁴ Institute for Immunology, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
⁵ Comprehensive Biomaterial Bank Marburg (CBBMR), Philipps-Universitat Marburg, Marburg, Germany.
⁶ Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, Justus Liebig Universitat, Giessen, Germany.
⁷ Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
⁸ Institute of Systems Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁹ Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
¹⁰ Institute of Biotechnology, Technische Universität, Berlin, Germany.
¹¹ German Rheumatism Research Center (DRFZ), An Institute of the Leibniz Association, Berlin, Germany.
¹² Department of Surgery, Johannes Gutenberg University, Mainz, Germany.
¹³ Division of Visceral, Thoracic and Vascular Surgery, Philipps-University Marburg, Marburg, Germany.
¹⁴ Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany.
¹⁵ Institute of Molecular Biology and Tumor Research (IMT), Philipps-University Marburg, Marburg, Germany.
¹⁶ Department of Hematology, Oncology and Immunology, Philipps University Marburg Faculty of Medicine, Marburg, Germany.
¹⁷ Institute for Medical Bioinformatics and Biostatistics, Philipps-University Marburg, Marburg, Germany.
¹⁸ Department of Diagnostic and Interventional Radiology, Heidelberg University, Heidelberg, Germany.
¹⁹ Institute of Pathology, JGU Mainz, Mainz, Germany.
²⁰ Research Center for Immunotherapy, University Medical Center Mainz, JGU-Mainz, Mainz, Germany.
²¹ Joint Unit Immunopathology, Institute of Pathology, University Medical Center, JGU-Mainz and TRON, Translational Oncology at the University Medical Center, JGU-Mainz, Mainz, Germany.
²² Institute of Systems Immunology, Philipps-University Marburg, Marburg, Germany magdalena.huber@staff.uni-marburg.de.

^# Contributed equally.

Abstract

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 Foxn1^nu/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 Foxn1^nu/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.

Keywords: cancer immunobiology; cytokines; immune response; inflammatory mechanisms; pancreatic cancer.

MeSH terms

CD8-Positive T-Lymphocytes
Cancer-Associated Fibroblasts* / metabolism
Carcinoma, Pancreatic Ductal* / pathology
Homeodomain Proteins
Humans
Interleukin-17 / metabolism
Pancreatic Neoplasms* / pathology

Substances

Interleukin-17
Homeodomain Proteins