ATP–NLRP3 inflammasome axis enhances the immunosuppressive effect of myeloid-derived suppressor cells

Abstract

The effectiveness of immune checkpoint inhibitors is diminished by the presence of myeloid-derived suppressor cells (MDSCs). Recent studies indicate that the NLR family pyrin domain-containing 3 (NLRP3) inflammasome regulates MDSC function, thereby reducing the efficacy of immune checkpoint inhibitors. However, the specific mechanism by which NLRP3 expression induces the immunosuppressive effects in MDSCs remains unclear. Here, we demonstrate that the adenosine triphosphate (ATP)–NLRP3 inflammasome axis enhances the immunosuppressive effects of MDSCs. We found that ATP increases the mRNA levels of immunosuppressive molecules in MDSCs, leading to the suppression of T cell proliferation. Additionally, we showed the efficacy of a novel immune checkpoint therapy that combines an ATP receptor inhibitor (P2X7 receptor inhibitor), an NLRP3 inhibitor, and an anti-PD-L1 antibody (Ab). This combination treatment significantly inhibited tumor growth compared to treatment with only the NLRP3 inhibitor and anti-PD-L1 Ab. These results suggest that the ATP–NLRP3 axis enhances the immunosuppressive effect of MDSCs. In conclusion, this study elucidates the mechanism through which MDSCs acquire immunosuppressive functions, potentially informing the development of novel cancer immunotherapies.