Therapeutic blockade of activin-A improves NK cell function and antitumor immunity

Jai Rautela, Laura F. Dagley, Carolina C. De Oliveira, 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

Research output: Contribution to journalArticleResearchpeer-review

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 languageEnglish
Article numberaat7527
Number of pages13
JournalScience Signaling
Volume12
Issue number596
DOIs
Publication statusPublished - 27 Aug 2019

Cite this

Rautela, J., Dagley, L. F., De Oliveira, C. C., Schuster, I. S., Hediyeh-Zadeh, S., Delconte, R. B., ... Souza-Fonseca-Guimaraes, F. (2019). Therapeutic blockade of activin-A improves NK cell function and antitumor immunity. Science Signaling, 12(596), [aat7527]. https://doi.org/10.1126/scisignal.aat7527
Rautela, Jai ; Dagley, Laura F. ; De Oliveira, Carolina C. ; Schuster, Iona S. ; Hediyeh-Zadeh, Soroor ; Delconte, Rebecca B. ; Cursons, Joseph ; Hennessy, Robert ; Hutchinson, Dana S. ; Harrison, Craig ; Kita, Badia ; Vivier, Eric ; Webb, Andrew I. ; Degli-Esposti, Mariapia A. ; Davis, Melissa J. ; Huntington, Nicholas D. ; Souza-Fonseca-Guimaraes, Fernando. / Therapeutic blockade of activin-A improves NK cell function and antitumor immunity. In: Science Signaling. 2019 ; Vol. 12, No. 596.
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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.",
author = "Jai Rautela and Dagley, {Laura F.} and {De Oliveira}, {Carolina C.} and Schuster, {Iona S.} and Soroor Hediyeh-Zadeh and Delconte, {Rebecca B.} and Joseph Cursons and Robert Hennessy and Hutchinson, {Dana S.} and Craig Harrison and Badia Kita and Eric Vivier and Webb, {Andrew I.} and Degli-Esposti, {Mariapia A.} and Davis, {Melissa J.} and Huntington, {Nicholas D.} and Fernando Souza-Fonseca-Guimaraes",
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Rautela, J, Dagley, LF, De Oliveira, CC, Schuster, IS, Hediyeh-Zadeh, S, Delconte, RB, Cursons, J, Hennessy, R, Hutchinson, DS, Harrison, C, Kita, B, Vivier, E, Webb, AI, Degli-Esposti, MA, Davis, MJ, Huntington, ND & Souza-Fonseca-Guimaraes, F 2019, 'Therapeutic blockade of activin-A improves NK cell function and antitumor immunity', Science Signaling, vol. 12, no. 596, aat7527. https://doi.org/10.1126/scisignal.aat7527

Therapeutic blockade of activin-A improves NK cell function and antitumor immunity. / Rautela, Jai; Dagley, Laura F.; De Oliveira, Carolina C.; Schuster, Iona S.; Hediyeh-Zadeh, Soroor; Delconte, Rebecca B.; Cursons, Joseph; Hennessy, Robert; Hutchinson, Dana S.; Harrison, Craig; Kita, Badia; Vivier, Eric; Webb, Andrew I.; Degli-Esposti, Mariapia A.; Davis, Melissa J.; Huntington, Nicholas D.; Souza-Fonseca-Guimaraes, Fernando.

In: Science Signaling, Vol. 12, No. 596, aat7527, 27.08.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Therapeutic blockade of activin-A improves NK cell function and antitumor immunity

AU - Rautela, Jai

AU - Dagley, Laura F.

AU - De Oliveira, Carolina C.

AU - Schuster, Iona S.

AU - Hediyeh-Zadeh, Soroor

AU - Delconte, Rebecca B.

AU - Cursons, Joseph

AU - Hennessy, Robert

AU - Hutchinson, Dana S.

AU - Harrison, Craig

AU - Kita, Badia

AU - Vivier, Eric

AU - Webb, Andrew I.

AU - Degli-Esposti, Mariapia A.

AU - Davis, Melissa J.

AU - Huntington, Nicholas D.

AU - Souza-Fonseca-Guimaraes, Fernando

PY - 2019/8/27

Y1 - 2019/8/27

N2 - 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.

AB - 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.

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