title: Adaptive NK Cells with Low TIGIT Expression Are Inherently Resistant to Myeloid-Derived Suppressor Cells.
abstract: Human cytomegalovirus (CMV)-induced adaptive natural killer (NK) cells display distinct phenotypic and functional characteristics, including properties of immune memory. We hypothesized that these cells may be more resistant to suppression mediated by immunoregulatory cell subsets, making them attractive for use in cancer therapy. Here we report that relative to conventional NK cells, adaptive NK cells express lower levels of the inhibitory receptor T-cell Ig and ITIM domain (TIGIT), which results in resistance to immune suppression mediated by myeloid-derived suppressor cells (MDSC), as derived from cytokine induction in normal blood or patients with myelodysplastic syndrome. In contrast, conventional NK cells were potently suppressed by MDSCs, an effect abrogated completely by TIGIT blockade. Mechanistically, TIGIT signaling in NK cells after MDSC coculture led to a decrease in the phosphorylation of ZAP70/Syk and ERK1/2. These effects were reversed by blocking TIGIT on NK cells or by inhibiting production of reactive oxygen species (ROS) by MDSCs, the latter of which upregulated the TIGIT ligand CD155 on MDSCs. Accordingly, the blunted cytotoxicity of NK cells cocultured with MDSCs against tumor cells could be reversed by blocking TIGIT or ROS production. Overall, our results show how adaptive NK cells arising in response to CMV infection can escape MDSC-mediated suppression, and defined TIGIT antagonists as a novel type of checkpoint inhibitor to enhance NK-cell-mediated responses against cancer and infection. Cancer Res; 76(19); 5696-706. ©2016 AACR.
authors: Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors: Dhifaf
authors: D
authors: Sarhan
authors: Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors: Frank
authors: F
authors: Cichocki
authors: Cancer Center, University of Minnesota Cancer Center, Minneapolis, Minnesota.
authors: Bin
authors: B
authors: Zhang
authors: Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
authors: Ashley
authors: A
authors: Yingst
authors: Center for International Blood and Marrow Transplant Research, Minneapolis, Minnesota.
authors: Stephen R
authors: SR
authors: Spellman
authors: Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors: Sarah
authors: S
authors: Cooley
authors: Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
authors: Michael R
authors: MR
authors: Verneris
authors: Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
authors: Bruce R
authors: BR
authors: Blazar
authors: Department of Medicine, University of Minnesota, Minneapolis, Minnesota. mille011@umn.edu.
authors: Jeffrey S
authors: JS
authors: Miller
mesh_terms: D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006801:Humans; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D009190:Myelodysplastic Syndromes / Q000276:immunology; D000072737:Myeloid-Derived Suppressor Cells / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D011971:Receptors, Immunologic / Q000502:physiology*; D011991:Receptors, Virus / Q000032:analysis; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000502:physiology
chemical_list: D017382:Reactive Oxygen Species; D011971:Receptors, Immunologic; D011991:Receptors, Virus; C534712:TIGIT protein, human; C066100:poliovirus receptor; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases