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

J Rautela; LF Dagley; CC De Oliveira; IS Schuster; S Hediyeh-Zadeh; RB Delconte; J Cursons; R Hennessy; DS Hutchinson; C Harrison; B Kita; E Vivier; AI Webb; MA Degli-Esposti; MJ Davis; ND Huntington; F Souza-Fonseca-Guimaraes

Journal article

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

J Rautela, LF Dagley, CC De Oliveira, IS Schuster, S Hediyeh-Zadeh, RB Delconte, J Cursons, R Hennessy, DS Hutchinson, C Harrison, B Kita, E Vivier, AI Webb, MA Degli-Esposti, MJ Davis, ND Huntington, F Souza-Fonseca-Guimaraes

Science Signaling | AMER ASSOC ADVANCEMENT SCIENCE | Published : 2019

DOI: 10.1126/scisignal.aat7527

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 prolif..

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University of Melbourne Researchers

Laura Dagley Author

Rebecca Delconte Author

Andrew Webb Author

Grants

Awarded by Horizon 2020 Framework Programme

Funding Acknowledgements

This work was supported by project grants from the National Health and Medical Research Council (NHMRC) of Australia (grants 1124784, 1066770, 1057852, and 1124907 to N.D.H.; grant 1140406 to F.S.-F.-G.; and NHMRC Program grant 1071822 to M.A.D.-E.). F.S.-F.-G. was supported by an NHMRC Early Career Fellowship (1088703), a National Breast Cancer Foundation (NBCF) Fellowship (PF-15-008), grants 1120725 and 1158085 awarded through the Priority-driven Collaborative Cancer Research Scheme, and the Cure Cancer Australia with the assistance of Cancer Australia. N.D.H. is an NHMRC CDF2 Fellow (1124788) and a recipient of a Melanoma Research Grant from the Harry J. Lloyd Charitable Trust, a Melanoma Research Alliance Young Investigator Award, a Tour De Cure research grant, an equipment grant from The Ian Potter Foundation, and a CLIP grant from Cancer Research Institute. M.A.D.-E. holds a NHMRC Principal Research Fellowship (1119298). This study was made possible through Victorian State Government Operational Infrastructure Support and the Australian Government NHMRC Independent Research Institute Infrastructure Support scheme.