Therapeutic blockade of activin-A improves NK cell function and antitumor immunity
Publication Year 2019-08-27,Volume 12,Issue #596,Page pii: eaat7527
Journal Title
Science Signaling
Publication Type
Journal Article
Natural killer (NK) cells are innate lymphocytes that play a major role in immunosurveillance against tumor initiation and metastatic spread. The signals and checkpoints that regulate NK cell fitness and function in the tumor microenvironment are not well defined. Transforming growth factor-beta (TGF-beta) is a suppressor of NK cells that inhibits interleukin-15 (IL-15)-dependent signaling events and increases the abundance of receptors that promote tissue residency. Here, we showed that NK cells express the type I activin receptor ALK4, which, upon binding to its ligand activin-A, phosphorylated SMAD2/3 to suppress IL-15-mediated NK cell metabolism. Activin-A impaired human and mouse NK cell proliferation and reduced the production of granzyme B to impair tumor killing. Similar to TGF-beta, activin-A also induced SMAD2/3 phosphorylation and stimulated NK cells to increase their cell surface expression of several markers of ILC1 cells. Activin-A also induced these changes in TGF-beta receptor-deficient NK cells, suggesting that activin-A and TGF-beta stimulate independent pathways that drive SMAD2/3-mediated NK cell suppression. Last, inhibition of activin-A by follistatin substantially slowed orthotopic melanoma growth in mice. These data highlight the relevance of examining TGF-beta-independent SMAD2/3 signaling mechanisms as a therapeutic axis to relieve NK cell suppression and promote antitumor immunity.
WEHI Research Division(s)
Immunology; Advanced Technology And Biology; Bioinformatics
PubMed ID
Terms of Use/Rights Notice
Refer to copyright notice on published article.

Creation Date: 2019-09-20 10:16:33
Last Modified: 2019-09-24 03:50:55
An error has occurred. This application may no longer respond until reloaded. Reload 🗙