急性髓系白血病中免疫检查点调控的硒依赖性调节

Acute myeloid leukemia (AML) is a hematologic malignancy with a 5-year survival rate of ~27 % among individuals aged 20 years and older. Despite advances in immune checkpoint inhibitor (ICI) therapies such as PD-1/PD-L1 blockade, leukemic cells still evade immunity, leading to relapse. PD-L1 on AML cells binds PD-1 on cytotoxic (CD8+) T cells, driving immune exhaustion and suppression. Given the link between low serum selenium (Se) and poor outcomes in hematologic malignancies, we investigated the mechanisms underlying the anti-leukemic effects of Se in a murine model of human AML. Supplementation with graded levels of dietary Se (as selenite at 0.08 ppm and 0.4 ppm of Se) led to a dose-dependent decrease in PDL1 and PD-1 expression in leukemic stem cells (LSCs) and CD8+ T-cells, respectively, mitigating T-cell exhaustion, resulting in better prognosis when compared to the AML mice on a Se-deficient diet. The effect of Se was mediated, in part, through the activation of GPR44, a GPCR, by prostaglandin J2, an endogenous ligand produced via Se-dependent eicosanoid class-switching mechanisms. Our studies highlight a novel dietary intervention strategy with Se supplementation that could potentially complement existing ICI therapy in AML.