IL-1R8 : a novel checkpoint regulating anti-tumor and anti-viral activity of NK cells

Abstract

IL-1R8 is an Interleukin-1 receptor family member that acts as a negative regulator of IL-1 family receptor and Toll-like receptor (TLR) signaling. Both murine and human NK cells express high levels of IL-1R8 but its functional role in this cell type has not been described so far. Natural Killer (NK) cells are innate lymphoid-derived cells and are able to recognize damaged, stressed, viral infected or tumor cells, which express ligands interacting with activating NK cell receptors. The expression of IL1R8 in NK cells prompted us to analyze its potential role in controlling NK cell effector functions. Expression analysis showed that IL-1R8 was acquired during differentiation in human and murine NK cells. IL-1R8 deficiency in the mouse was associated with higher frequency and absolute number of mature NK cells in blood, spleen, bone marrow and liver. Moreover, IL-1R8 deficient NK cells display an increased Interferonγ (IFNγ), Granzyme B and Fas ligand expression and degranulation. IL-18, which is a key regulator of NK cell activities and can be targeted by IL-1R8, was responsible for this phenotype. Indeed, IL-1R8 regulated IL-18 axis during NK cell differentiation and activation and IL-18-dependent activation of mTOR and JNK pathways increased in IL-1R8-deficient NK cells. To assess the role of IL-1R8 in NK cells in pathology, we used models of 3-methylcholanthrene (MCA)-induced lung metastasis, colon cancer-derived liver metastasis and diethylnitrosamine (DEN)-induced hepatocellular carcinoma. The number and dimension of liver and lung metastasis and the liver disease severity were significantly reduced in Il1r8-/- mice. The depletion of NK cells in these models totally abrogated the protection observed in Il1r8-/- mice. Finally, we investigated the role of IL-1R8 in NK cell antiviral activity, in a model of murine cytomegalovirus (MCMV) infection. Il1r8-/- mice showed an improved virus control in the liver and the protection was associated with enhanced NK cell degranulation and IFNγ production. The adoptive transfer of Il1r8-/- NK cells conferred protection in both metastasis and viral infection models. Collectively, these results showed that IL-1R8 played a non-redundant role in the regulation of NK cell development and effector functions by tuning IL-18-dependent activities. IL-1R8 therefore emerges as a novel checkpoint molecule modulating NK cell antitumoral and antiviral potential. Preclinical models showed that the inactivation of IL-1R8 unleashed NK cell effector functions, unveiling IL-1R8 as a potential immunotherapy target in the context of cancer and viral infections.