Tissue resident iNKT17 cells facilitate cancer cell extravasation in liver metastasis via interleukin-22

Anastasios D. Giannou*, Jan Kempski, Ahmad Mustafa Shiri, Jöran Lücke, Tao Zhang, Lilan Zhao, Dimitra E. Zazara, Filippo Cortesi, Kristoffer Riecken, Maria Carolina Amezcua Vesely, Jun Siong Low, Hao Xu, Eleanna Kaffe, Laura Garcia-Perez, Theodora Agalioti, Yoshito Yamada, Wolfgang Jungraithmayr, Ehud Zigmond, Karl Frederick Karstens, Babett SteglichJonas Wagner, Leonie Konczalla, Antonella Carambia, Kornelius Schulze, Johann von Felden, Peter May, Daria Briukhovetska, Tanja Bedke, Leonie Brockmann, Sarah Starzonek, Tobias Lange, Claudia Koch, Sabine Riethdorf, Penelope Pelczar, Marius Böttcher, Morsal Sabihi, Francis J. Huber, Matthias Reeh, Julia Kristin Grass, Ramez Wahib, Hannes Seese, Björn Ole Stüben, Mohammad Fard-Aghaie, Anna Duprée, Pasquale Scognamiglio, Gabriel Plitzko, Jan Meiners, Shiwa Soukou, Agnes Wittek, Caroline Manthey, Ioannis C. Maroulis, Petra C. Arck, Daniel Perez, Bin Gao, Sotirios G. Zarogiannis, Till Strowig, Renata Pasqualini, Wadih Arap, Javier Suárez Gosálvez, Sebastian Kobold, Immo Prinz, Andreas H. Guse, Michael Tachezy, Tarik Ghadban, Asmus Heumann, Jun Li, Nathaniel Melling, Oliver Mann, Jakob R. Izbicki, Klaus Pantel, Udo Schumacher, Ansgar W. Lohse, Richard A. Flavell, Nicola Gagliani, Samuel Huber*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


During metastasis, cancer cells invade, intravasate, enter the circulation, extravasate, and colonize target organs. Here, we examined the role of interleukin (IL)-22 in metastasis. Immune cell-derived IL-22 acts on epithelial tissues, promoting regeneration and healing upon tissue damage, but it is also associated with malignancy. Il22-deficient mice and mice treated with an IL-22 antibody were protected from colon-cancer-derived liver and lung metastasis formation, while overexpression of IL-22 promoted metastasis. Mechanistically, IL-22 acted on endothelial cells, promoting endothelial permeability and cancer cell transmigration via induction of endothelial aminopeptidase N. Multi-parameter flow cytometry and single-cell sequencing of immune cells isolated during cancer cell extravasation into the liver revealed iNKT17 cells as source of IL-22. iNKT-cell-deficient mice exhibited reduced metastases, which was reversed by injection of wild type, but not Il22-deficient, invariant natural killer T (iNKT) cells. IL-22-producing iNKT cells promoting metastasis were tissue resident, as demonstrated by parabiosis. Thus, IL-22 may present a therapeutic target for prevention of metastasis.

Original languageEnglish
Pages (from-to)125-142.e12
Issue number1
StatePublished - 10 Jan 2023


  • IL-22
  • cancer cell extravasation
  • endothelial cells
  • extravasation
  • metastasis
  • metastasis formation
  • tissue resident cells


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