DOI: 10.1101/454801Oct 29, 2018Paper

Therapeutic blockade of Activin-A improves NK cell function and anti-tumor immunity

BioRxiv : the Preprint Server for Biology
Jai RautelaFernando Souza-Fonseca-Guimaraes

Abstract

Natural killer (NK) cells are innate lymphocytes that play a major role in immunosurveillance against tumor initiation and metastasis spread. Signals and checkpoints that regulate NK cell fitness and function in the tumor microenvironment are not well defined. Transforming grow factor (TGF)-beta is a recognized suppressor of NK cells that inhibits IL-15 dependent signaling events and induces cellular transdifferentiation, however the role of other SMAD signaling pathways in NK cells is unknown. In this report, we show that NK cells express the type I Activin receptor, ALK4, which upon binding its ligand Activin-A, phosphorylates SMAD2/3 to efficiently suppress IL-15-mediated NK cell metabolism. Activin-A impairs human and mouse NK cell proliferation and downregulates intracellular granzyme B levels to impair tumor killing. Similar to TGF-beta, Activin-A also induced SMAD2/3 phosphorylation and drove NK cells to upregulate several ILC1-like surface markers including CD69, TRAIL and CD49a. Activin-A also induced these changes on TGF-beta receptor deficient NK cells, highlighting that Activin-A and TGF-beta are independent pathways that drive SMAD2/3-mediated NK cell suppression. Finally, therapeutic inhibition of Activin-A by Fol...Continue Reading

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