Tumor suppressor miR-34a targets PD-L1 and functions as a potential immunotherapeutic target in acute myeloid leukemia.

Abstract

miRNA (miR) 34a has been shown to modulate critical gene transcripts involved in tumorigenesis, but its role in tumor-mediated immunosuppression is largely unknown. PD-L1 plays an important role in immune responses, however, presently its transcriptional regulatory mechanisms are not well understood. In the present study, we analyzed the expression of PD-L1 and miR-34a in 44 acute myeloid leukemia (AML) samples, and observed an inverse correlation between PD-L1 and miR-34a expression. Overexpression of miR-34a in HL-60 and Kasumi-1 cells blocked PD-L1 expression, and reduced PD-L1 surface expression. Using luciferase reporter assay and mutagenesis, we identified miR-34a as a putative binder of the PD-L1-3'UTR. Surface expression of PD-L1 induced by chemotherapeutic agents could also be reversed by miR-34a; furthermore, PD-L1 specific T cell apoptosis was reduced as well following miR-34a transfection. We also found that there is a positive feedback between PD-L1 expression and AKT activation. Our data suggest that miR-34a can regulate PD-L1 expression by targeting PD-L1 mRNA, and our present findings shed new light on the complex regulation of PD-L1 in human tumors, and on miR-34a in cancer immuno-based therapy.