Aiming to uncover novel approaches to utilize NK cells, Sarhan et al. found that while FcεRγ+NKG2C- canonical NK cells are susceptible to Treg suppression, FcεRγ-NKG2C+ adaptive NK cells are resistant to it. Tregs secrete IL-37, which binds the inhibitory receptor IL1R8 on canonical NK cells, exerting functional suppression by downregulating TIM-3 (which acts as an activating receptor on NK cells) and upregulating PD-1 and IL1R8. Adaptive NK cells were found to be resistant to Treg suppression due to significantly lower expression of IL1R8 compared to canonical NK cells.
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 (Tregs), 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+ FcepsilonRgamma-NKG2C+ adaptive (CD56+CD3-) NK cells that expand in cytomegalovirus (CMV)-exposed individuals. Specifically, Tregs suppressed canonical but not adaptive NK-cell proliferation, IFNgamma production, degranulation, and cytotoxicity. Treg-mediated suppression was associated with canonical NK-cell downregulation of TIM3, a receptor that activates NK-cell IFNgamma 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.