Type 2 innate lymphoid cells impair IL-33-mediated tumor suppression

Abstract

Abstract Although a number of studies have recently explored the contribution of the adaptive immunity in interleukin 33 (IL-33)-mediated antitumor effects, the involvement of innate immunity has been weakly characterized. Using Rag1−/− mice (lacking T and B lymphocytes), we show here that either systemic administration of recombinant IL-33 or ectopic expression of IL-33 in melanoma cells is sufficient to significantly delay tumor growth independent of adaptive antitumor immunity. We have demonstrated that IL-33-mediated antitumor effects rely on expansion and activation of NK cells. Concurrently, IL-33 also promoted the expansion of active type 2 innate lymphoid cells (ILC2s), via its receptor, ST2. Elevated ILC2 presence coincided with decreased NK activation and cytotoxicity, and resulted in increased tumor growth, indicating a protumor role for ILC2s. IL-33-induced ILC2 activity elicited greater expression of the immunosuppressive ecto-enzyme CD73. Removal of CD73 from ILC2s in culture with NK cells resulted in markedly increased activation levels in NK cells, providing a potential mechanism by which ILC2s may suppress NK cell-mediated tumor killing. Thus, our data reveal an important contribution of IL-33-induced ILC2 to tumor growth by weakening NK cell activation and tumor killing, independent of adaptive immunity.