IL1R8 May Be a Natural Killer Cell Checkpoint Protein

Natural killer (NK) cells are a component of the innate immune system that promote resistance to hematopoietic neoplasms; however, only minor roles for NK cells have been demonstrated in solid tumors. Molgora, Bonavita, and colleagues identified the interleukin-1 receptor 8 (IL1R8) as a checkpoint protein in NK cells that regulates antitumor activity in solid tumors. IL1R8 was highly expressed in NK cells compared with other leukocytes and monocyte-derived macrophages, and its expression increased during NK cell maturation. The peripheral blood of Il1r8^−/− mice had an increase in NK cell number and maturity, despite the same number of NK precursor cells as wild-type mice. IL1R8-deficient NK cells also exhibited more sustained activation following stimulation and produced increased levels of IFNγ. Inhibiting IL18 abolished the enhanced NK cell maturation in Il1r8^−/− cells, suggesting that IL1R8 negatively regulates IL18. Consistent with these findings, IL18-mediated activation of downstream MyD88 signaling was increased in Il1r8^−/− cells. RNA sequencing revealed that IL1R8 deficient cells had increased expression of activation pathway genes, adhesion molecules involved in cell-to-cell interactions and cytotoxicity, and chemokines such as CCL4. Further, as in the mouse cells, IL1R8 served as a negative regulator of human NK cells. The liver has a high frequency of NK cells, and IL1R8 deficiency protected against hepatocellular carcinoma in carcinogen-challenged mice. Depleting NK cells abolished the protection conferred by IL1R8 loss, indicating that NK were responsible for preventing tumorigenesis. Additionally, IL1R8 loss suppressed metastasis in mouse tumor models, and also reduced viral infections. In addition to suggesting that NK cells may have the potential to suppress solid tumor growth and metastasis, these findings demonstrate that IL1R8 is an NK cell checkpoint protein that may be inhibited to promote antitumor activity.

Molgora M, Bonavita E, Ponzetta A, Riva F, Barbagallo M, Jaillon S, et al. IL-1R8 is a checkpoint in NK cells regulating anti-tumour and anti-viral activity. Nature 2017;551:110–4.

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