PD-L1 Is Expressed and Promotes the Expansion of Regulatory T Cells in Acute Myeloid Leukemia

Intratumoral accumulation of CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells occurs in acute myeloid leukemia (AML), but little is known about the role of tumor cells themselves in this process. Here, we showed that an immune checkpoint PD-L1 expressed by AML cells promoted the conversion and expansion of Treg cells sustaining high expression of Foxp3 and PD-1 as well as a suppressive function. Furthermore, an AML cell line HEL overexpressed PD-L1 promoted the conversion and expansion of Treg cells and CD4(+)PD-1(+)Foxp3(+) T (PD-1(+)Treg) cells from the conventional CD4(+) T cells. CD4(+)CD25(high)PD-1(+) T cells secreted more IL-10 production than CD4(+)CD25(high)PD-1(−) T cells. IL-35, another cytokine secreted by Treg cells, promoted the proliferation of HL-60 cells and enhanced chemoresistance to cytarabine. Blockade of PD-1 signaling using anti-PD-L1 antibody dramatically impaired the generation of Treg cells and sharply retarded the progression of a murine AML model injected with C1498 cells. The frequency of intratumoral PD-1(+) Treg cells was capable of predicting patient survival in patients with AML. In conclusion, our data suggest that PD-L1 expression by AML cells may directly drive Treg cell expansion as a mechanism of immune evasion and the frequency of PD-1(+) Treg cells is a potential prognostic predictor in patients with AML.