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: Dhifaf Sarhan, Frank Cichocki, Bin Zhang, Ashley Yingst, Stephen R Spellman, Sarah Cooley, Michael R Verneris, Bruce R Blazar, Jeffrey S Miller
• Journal: Cancer research (Cancer Res) Vol. 76 Issue 19 Pg. 5696-5706 (10 01 2016) ISSN: 1538-7445 [Electronic] United States
• PMID: 27503932 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Reactive Oxygen Species
• Receptors, Immunologic
• Receptors, Virus
• TIGIT protein, human
• poliovirus receptor
• ZAP-70 Protein-Tyrosine Kinase
• ZAP70 protein, human
• Extracellular Signal-Regulated MAP Kinases

Topics

• Extracellular Signal-Regulated MAP Kinases (physiology)
• Humans
• Immunotherapy
• Killer Cells, Natural (immunology)
• Lymphocyte Activation
• Myelodysplastic Syndromes (immunology)
• Myeloid-Derived Suppressor Cells (immunology)
• Reactive Oxygen Species (metabolism)
• Receptors, Immunologic (physiology)
• Receptors, Virus (analysis)
• ZAP-70 Protein-Tyrosine Kinase (physiology)