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

Therapeutic blockade of activin-A improves NK cell function and antitumor immunity. Sci Signal. 2019 Aug 27;12(596): Authors: 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 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 dr...
Source: Science Signaling - Category: Biomedical Science Authors: Tags: Sci Signal Source Type: research