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

Immunity. 2023 Jan 10;56(1):125-142.e12. doi: 10.1016/j.immuni.2022.12.014.


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.

Keywords: ANPEP; IL-22; cancer cell extravasation; endothelial cells; extravasation; metastasis; metastasis formation; tissue resident cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Colorectal Neoplasms / metabolism
  • Endothelial Cells / metabolism
  • Interleukins* / metabolism
  • Liver Neoplasms* / pathology
  • Liver Neoplasms* / secondary
  • Mice
  • Mice, Inbred C57BL
  • Natural Killer T-Cells* / metabolism


  • interleukin-22
  • Interleukins