IL-18 Enhances Immunosuppressive Responses by Promoting Differentiation into Monocytic Myeloid-Derived Suppressor Cells

Abstract

Myeloid-derived suppressor cells (MDSCs) are major immunosuppressive cells that lead to T cell defects in cancer. IL-18 is important in inflammatory and immune responses. IL-18 has been reported to have a dual effect on tumor progression, as it not only stimulates host immune responses, but also exerts procancer effects by inducing immune escape and angiogenesis. In the present study, we investigated the effect of IL-18 on MDSCs and found that IL-18 treatment significantly increased the percentage and the absolute number of monocytic MDSCs (M-MDSCs) via differentiation of CD11b− bone marrow progenitor cells. IL-18–induced MDSCs showed enhanced suppression of T cell proliferation and IFN-γ production along with a dramatic increase of M-MDSC suppressive function, including NO production and arginase 1 expression. Although IL-18 decreased the number of granulocytic MDSCs (G-MDSCs) in a concentration-dependent manner, we found that the absolute number of G-MDSCs and their reactive oxygen species production remained unchanged. Additionally, we demonstrated that IL-18–induced M-MDSCs have a more potent suppressive effect on T cell responses with lower IFN-γ production than do G-MDSCs, suggesting that the increased suppressive effect observed in our study resulted from M-MDSCs. Furthermore, in vivo administration of IL-18 significantly increased the accumulation of M-MDSCs in the tumor microenvironment. Taken together, our findings indicate that IL-18 specifically enhances the differentiation and function of M-MDSCs, leading to immunosuppression.