Invited Speaker Presentation Eradicate Cancer 2020

Therapeutic blockade of TGF-β superfamily members improves NK cell function and anti-tumor immunity (70102)

Fernando Guimaraes 1 2 , Joseph Cursons 3 , Laura F Dagley 4 , Nicholas D Huntington 2 5
  1. The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Queensland, Australia
  2. Division of Molecular Immunology, The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Parkville, Australia
  3. Division of Bioinformatics, The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, Faculty of Medicine, Dentistry and Health Sciences. University of Melbourne , Parkville, Australia
  4. Systems Biology and Personalized Medicine Division, The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Parkville, Australia
  5. Biomedicine Discovery Institute and the Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia

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)-β is a recognized suppressor of NK cells that inhibits IL-15-dependent signaling and induces cellular transdifferentiation. Computational analyses of an NK cell gene signature in metastatic melanoma showed that higher NK cell infiltration is associated with improved patient survival and this effect is ablated in patients where there is evidence of active TGF-β signaling. This suggests that a subset of patients would benefit from therapies that can prevent pSMAD2/3, however, in NK cells the role of other SMAD signaling pathways that act downstream from the TGF-β superfamily is unknown. Here, we show that NK cells also 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-β, Activin-A also induces SMAD2/3 phosphorylation and drives NK cells to upregulate several innate lymphoid cell (ILC)1-like surface markers. Further, Activin-A also induces these changes on TGF-β receptor deficient NK cells, highlighting that Activin-A and TGF-β are independent pathways that can drive SMAD2/3-mediated NK cell suppression. Finally, therapeutic inhibition of Activin-A by Follistatin significantly slows orthotopic melanoma growth in mice. These data highlight the relevance of examining TGF-β-independent SMAD2/3 signaling mechanisms as a novel therapeutic axis to relieve NK cell suppression and promote tumor immunity.