IL-17A-producing NKp44(−) group 3 innate lymphoid cells accumulate in Familial Adenomatous Polyposis duodenal tissue

Kim M. Kaiser, Jan Raabe, Michael ToVinh, Gudrun Hack, Sarah Ahmad, Niko Müller, Julia Cassella, Sofia I. Walravens, Paula Alfaro, Lauren Arias Garcia, Dominik J. Kaczmarek, Tim Marwitz, Felix Goeser, Hans Dieter Nischalke, Philipp Lutz, Nils Sommer, Tim Vilz, Marieta Toma, Susanne Steiner, Oliver Hommerding, Johannes Oldenburg, Michael Hölzel, Sebastian Kadzik, Alexander Maas, Jonas Eckrich, Philipp Zumfelde, Farhad Shakeri, Svetozar Nesic, Andreas Buness, Emilia Caro, Matthias Becker, Marc D. Beyer, Thomas Ulas, Anna C. Aschenbrenner, Lisa M. Steinheuer, Kevin Thurley, Sandy Kroh, Ralf Uecker, Anja E. Hauser, Florian N. Gohr, Florian I. Schmidt, Danni Wang, Kathrin Held, Olga Baranov, Christof Geldmacher, Christian P. Strassburg, Robert Hüneburg, Benjamin Krämer () and Jacob Nattermann ()
Additional contact information
Kim M. Kaiser: University Hospital Bonn
Jan Raabe: University Hospital Bonn
Michael ToVinh: University Hospital Bonn
Gudrun Hack: University Hospital Bonn
Sarah Ahmad: University Hospital Bonn
Niko Müller: University Hospital Bonn
Julia Cassella: University Hospital Bonn
Sofia I. Walravens: University Hospital Bonn
Paula Alfaro: University Hospital Bonn
Lauren Arias Garcia: University Hospital Bonn
Dominik J. Kaczmarek: University Hospital Bonn
Tim Marwitz: University Hospital Bonn
Felix Goeser: University Hospital Bonn
Hans Dieter Nischalke: University Hospital Bonn
Philipp Lutz: University Hospital Bonn
Nils Sommer: University Hospital Bonn
Tim Vilz: University Hospital Bonn
Marieta Toma: University Hospital Bonn
Susanne Steiner: University Hospital Bonn
Oliver Hommerding: University Hospital Bonn
Johannes Oldenburg: University Hospital Bonn
Michael Hölzel: University Hospital Bonn
Sebastian Kadzik: University Hospital Bonn
Alexander Maas: University Hospital Bonn
Jonas Eckrich: University Medical Center Mainz
Philipp Zumfelde: Gastroenterology
Farhad Shakeri: University of Bonn
Svetozar Nesic: University of Bonn
Andreas Buness: University of Bonn
Emilia Caro: Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)
Matthias Becker: Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)
Marc D. Beyer: Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)
Thomas Ulas: Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)
Anna C. Aschenbrenner: Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)
Lisa M. Steinheuer: University Hospital Bonn
Kevin Thurley: University Hospital Bonn
Sandy Kroh: Leibniz Association
Ralf Uecker: Charité-Universitätsmedizin Berlin Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Anja E. Hauser: Charité-Universitätsmedizin Berlin Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Florian N. Gohr: University of Bonn
Florian I. Schmidt: University of Bonn
Danni Wang: LMU Munich
Kathrin Held: LMU Munich
Olga Baranov: LMU Munich
Christof Geldmacher: LMU Munich
Christian P. Strassburg: University Hospital Bonn
Robert Hüneburg: University Hospital Bonn
Benjamin Krämer: University Hospital Bonn
Jacob Nattermann: University Hospital Bonn

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Familial adenomatous polyposis (FAP) is an inherited gastrointestinal syndrome associated with duodenal adenoma formation. Even among carriers of the same genetic variant, duodenal phenotypes vary, indicating that additional factors, such as the local immune system, play a role. We observe an increase in duodenal IL-17A(+)NKp44(−) innate lymphoid type 3 cell (ILC3) in FAP, localized near the epithelium and enriched in adenomas and carcinomas. Elevated IL1B, IL23A, and DLL4 transcript levels correlate with IL-17A(+)NKp44(−)ILC3 accumulation, and in vitro studies with duodenal organoids confirmed this relationship. Bulk RNA sequencing reveals upregulated Reactive oxygen species (ROS)-inducing enzymes DUOX2 and DUOXA2 in FAP adenomas. IL-17A-stimulated FAP organoids show increased DUOX2/DUOXA2 expression, Duox2 protein, and ROS production, leading to DNA damage, suggesting a mechanism by which these immune cells promote tumorigenesis. These findings suggest IL-17A(+)NKp44(–)ILC3s may contribute to a local environment that makes the epithelium more submissive for oncogenic transformation in FAP.

Date: 2025
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DOI: 10.1038/s41467-025-58907-y

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