IL17A-Mediated Endothelial Breach Promotes Metastasis Formation

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• The role of the Interleukin-23/Interleukin-17A (IL-23/IL-17A) signaling pathway in cancer is debated.
• Some studies suggest IL-17A-producing T helper 17 (TH17) cells suppress tumor growth, while others indicate IL-17A and IL-23 promote tumor progression.

Purpose of the Study:

• To systematically evaluate the impact of IL-17A-secreting lymphocytes on lung metastasis in murine models.
• To elucidate the cellular sources of IL-17A within lung tumors and its specific effects on endothelial cells.

Main Methods:

• Utilized genetic fate mapping to identify IL-17A-producing cells in lung metastases.
• Employed various murine tumor models, including Il17a knockout mice.
• Investigated the effects of IL-17A on lung endothelial cells in vivo and in transgenic models targeting IL-17A to the endothelium.

Main Results:

• IL-17A was predominantly secreted by gamma delta T cells, not TH17 cells, in lung metastases.
• Mice lacking Il17a consistently showed fewer pulmonary tumor colonies.
• IL-17A increased blood vessel permeability and expression of adhesion molecules (E-selectin, VCAM-1) on lung endothelial cells.
• Targeting IL-17A to the endothelium increased tumor foci formation.
• IL-17A directly impaired endothelial barrier integrity, promoting tumor cell transmigration.

Conclusions:

• IL-17A plays a pro-metastatic role in lung cancer by compromising endothelial barrier function.
• Gamma delta T cells are a major source of IL-17A driving lung metastasis.
• Targeting the IL-17A pathway could be a therapeutic strategy to inhibit lung metastasis.