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https://hdl.handle.net/2440/134694
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Type: | Journal article |
Title: | Therapeutic blockade of activin-A improves NK cell function and antitumor immunity |
Author: | Rautela, J. Dagley, L.F. de Oliveira, C.C. Schuster, I.S. Hediyeh-Zadeh, S. Delconte, R.B. Cursons, J. Hennessy, R. Hutchinson, D.S. Harrison, C. Kita, B. Vivier, E. Webb, A.I. Degli-Esposti, M.A. Davis, M.J. Huntington, N.D. Souza-Fonseca-Guimaraes, F. |
Citation: | Science Signaling, 2019; 12(596):eaat7527-1-eaat7527-14 |
Publisher: | American Association for the Advancement of Science |
Issue Date: | 2019 |
ISSN: | 1937-9145 1937-9145 |
Statement of Responsibility: | Jai Rautela, Laura F. Dagley, Carolina C. deOliveira, Iona S. Schuster, Soroor Hediyeh-Zadeh, Rebecca B. Delconte, Joseph Cursons, Robert Hennessy, Dana S. Hutchinson, Craig Harrison, Badia Kita, Eric Vivier, Andrew I. Webb, Mariapia A. Degli-Esposti, Melissa J. Davis, Nicholas D. Huntington, Fernando Souza-Fonseca-Guimaraes |
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-β (TGF-β) 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-β, 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-β receptor-deficient NK cells, suggesting that activin-A and TGF-β 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-β-independent SMAD2/3 signaling mechanisms as a therapeutic axis to relieve NK cell suppression and promote antitumor immunity. |
Keywords: | activin-A; Natural Killer cell |
Rights: | © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works |
DOI: | 10.1126/scisignal.aat7527 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1121784 http://purl.org/au-research/grants/nhmrc/1066770 http://purl.org/au-research/grants/nhmrc/1057852 http://purl.org/au-research/grants/nhmrc/1124907 http://purl.org/au-research/grants/nhmrc/1140406 http://purl.org/au-research/grants/nhmrc/1071822 http://purl.org/au-research/grants/nhmrc/1088703 http://purl.org/au-research/grants/nhmrc/1124788 http://purl.org/au-research/grants/nhmrc/1119298 |
Published version: | http://dx.doi.org/10.1126/scisignal.aat7527 |
Appears in Collections: | Medicine publications |
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