Research ArticleImmunology

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

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Science Signaling  27 Aug 2019:
Vol. 12, Issue 596, eaat7527
DOI: 10.1126/scisignal.aat7527

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Enhancing NK cells

Natural killer (NK) cells are innate immune cells with a critical role in antitumor immunity. In the tumor microenvironment, the cytokine transforming growth factor–β (TGF-β) acts through its receptor to promote the differentiation of NK cells into a less suppressive cell type, thus inhibiting antitumor immunity. Rautela et al. showed that activin-A, another member of the TGF-β family, had similar effects on both mouse and human NK cells, although in a TGF-β receptor–independent manner. Inhibition of activin-A reduced orthotopic melanoma growth in mice, suggesting that targeting this pathway could therapeutically enhance NK cell function and antitumor immunity.

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.

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