Projects per year
Abstract
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- (TGF-) 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-, 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- receptor-deficient NK cells, suggesting that activin-A and TGF- 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-independent SMAD2/3 signaling mechanisms as a therapeutic axis to relieve NK cell suppression and promote antitumor immunity.
Original language | English |
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Article number | aat7527 |
Number of pages | 14 |
Journal | Science Signaling |
Volume | 12 |
Issue number | 596 |
DOIs | |
Publication status | Published - 27 Aug 2019 |
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Dive into the research topics of 'Therapeutic blockade of activin-A improves NK cell function and antitumor immunity'. Together they form a unique fingerprint.Projects
- 2 Curtailed
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Research Fellowship: Immunoregulation and immunity to viral infection
Degli-Esposti, M. (Investigator 01)
NHMRC National Health and Medical Research Council
1/01/17 → 9/10/20
Project: Research
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Immunological therapies for cancer, chronic infection and autoimmunity
Thomas, R. (Investigator 01), Hill, G. (Investigator 02), Frazer, I. (Investigator 03), Brown, M. (Investigator 04), Degli-Esposti, M. (Investigator 05) & Hugenholtz, P. (Investigator 06)
NHMRC National Health and Medical Research Council
1/01/15 → 30/12/19
Project: Research