Adaptive NK cells with low TIGIT expression are inherently resistant to myeloid-derived suppressor cells

Dhifaf Sarhan, Frank Cichocki, Bin Zhang, Ashley Yingst, Stephen R. Spellman, Sarah Cooley, Michael R. Verneris, Bruce R. Blazar, Jeffrey S. Miller

Research output: Contribution to journalArticlepeer-review

77 Scopus citations

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 inNKcells afterMDSC 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.

Original languageEnglish (US)
Pages (from-to)5696-5706
Number of pages11
JournalCancer Research
Volume76
Issue number19
DOIs
StatePublished - Oct 1 2016

Bibliographical note

Funding Information:
This work was supported by a fellowship to D. Sarhan from Karolinska Institutet, Sweden, and the following NIH grants: P01 CA111412 (J.S. Miller, S. Cooley, M.R. Verneris), P01 CA65493 (J.S. Miller, S. Cooley, M.R. Verneris, B.R. Blazar), R35 CA197292 (J.S. Miller, S. Cooley, M.R. Verneris), R01 HL122216 (J.S. Miller), R01 AI34495 (B.R. Blazar), and R01 CA72669 (B.R. Blazar). The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA076518 from the National Cancer Institute, the NHLBI, and the NIAID.

Publisher Copyright:
© 2016 AACR.

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