RT Journal Article
SR Electronic
T1 Adaptive NK Cells Resist Regulatory T-cell Suppression Driven by IL37
JF Cancer Immunology Research
JO Cancer Immunol Res
FD American Association for Cancer Research
SP 766
OP 775
DO 10.1158/2326-6066.CIR-17-0498
VO 6
IS 7
A1 Sarhan, Dhifaf
A1 Hippen, Keli L.
A1 Lemire, Amanda
A1 Hying, Skyler
A1 Luo, Xianghua
A1 Lenvik, Todd
A1 Curtsinger, Julie
A1 Davis, Zachary
A1 Zhang, Bin
A1 Cooley, Sarah
A1 Cichocki, Frank
A1 Blazar, Bruce R.
A1 Miller, Jeffrey S.
YR 2018
UL http://cancerimmunolres.aacrjournals.org/content/6/7/766.abstract
AB Natural killer (NK) cells are capable of fighting viral infections and cancer. However, these responses are inhibited by immune suppressor cells in the tumor microenvironment. Tumor progression promotes the recruitment and generation of intratumoral regulatory T cells (Treg), associated with a poor prognosis in cancer patients. Here, we show that canonical NK cells are highly susceptible to Treg-mediated suppression, in contrast to highly resistant CD57+ FcεRγ−NKG2C+ adaptive (CD56+CD3−) NK cells that expand in cytomegalovirus exposed individuals. Specifically, Tregs suppressed canonical but not adaptive NK-cell proliferation, IFNγ production, degranulation, and cytotoxicity. Treg-mediated suppression was associated with canonical NK-cell downregulation of TIM3, a receptor that activates NK-cell IFNγ production upon ligand engagement, and upregulation of the NK-cell inhibitory receptors PD-1 and the IL1 receptor family member, IL1R8 (SIGIRR or TIR8). Treg production of the IL1R8 ligand, IL37, contributed to the phenotypic changes and diminished function in Treg-suppressed canonical NK cells. Blocking PD-1, IL1R8, or IL37 abrogated Treg suppression of canonical NK cells while maintaining NK-cell TIM3 expression. Our data uncover new mechanisms of Treg-mediated suppression of canonical NK cells and identify that adaptive NK cells are inherently resistant to Treg suppression. Strategies to enhance the frequency of adaptive NK cells in the tumor microenvironment or to blunt Treg suppression of canonical NK cells will enhance the efficacy of NK-cell cancer immunotherapy. Cancer Immunol Res; 6(7); 766–75. ©2018 AACR.