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

The crosstalk among the immune system, cancer cells and the tissue microenvironment is fundamental for the emergence of organ-specific niches that facilitate metastasis formation. Here, we studied the involvement of IL-22, which is known to be produced by immune cells and to act on the tissue, in mediating this crosstalk and thus metastasis formation. We found that Il22-deficient mice and mice treated with an IL-22 antibody are protected from liver and lung metastasis formation, while over expression of IL-22 promoted metastasis formation. Mechanistically, IL-22 acted on endothelial cells thereby promoting endothelial permeability and cancer cell transmigration via induction of endothelial aminopeptidase N. Finally, tissue resident iNKT17 cells were the key source of IL-22 in the liver. Thus, targeting tissue resident immune cells derived IL-22 represents a potential therapeutic target in metastasis formation. Liver metastasis can be induced in mice by intrasplenic injection of cancer cells. We used single cell sequencing to study IL-22 expression by leukocytes in the liver before and 12h after intrasplenic injection.