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

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. [Display omitted] •Il22-deficient mice are protected against metastasis formation•IL-22 neutralization blocks cancer cell extravasation•IL-22 acts on endothelial cells, promoting cancer cell extravasation via ANPEP induction•Tissue resident iNKT17 cells are the key IL-22 source during cancer cell extravasation Interleukin-22 (IL-22) is produced by immune cells and promotes tissue repair and regeneration; however, in malignancy, IL-22 can promote tumor growth. Giannou et al. find that tissue resident iNKT17 cells produce IL-22 and promote cancer cell extravasation through regulation of aminopeptidase N. Neutralization of IL-22 inhibits metastasis formation, suggesting therapeutic avenues for cancer treatment.