Myeloid maturation potentiates STAT3-mediated atypical IFN-? signaling and upregulation of PD-1 ligands in AML and MDS.

ABSTRACT: Interferon (IFN)-? is the major mediator of anti-tumor immune responses; nevertheless, cancer cells use intrigue strategies to alter IFN-? signaling and avoid elimination. Understanding the immune regulatory mechanisms employed by acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cells upon exposure to IFN-? is critical for development of immunotherapy and checkpoint blockade therapy approaches. This study aims to explore the influence of myeloid maturation on IFN-?-induced PD-L1 and PD-L2 expression and on pro-leukemogenic transcription factor STAT3 signaling in AML and MDS. Stimulation of myeloid blasts' maturation by all-trans retinoic acid (ATRA) or 1?,25-dihydroxyvitamin D3 (vitamin D) increased the CD11b+ fraction that expressed PD-1 ligands in response to IFN-?. Intriguingly, STAT3 pathway was potently induced by IFN-? and strengthened upon prolonged exposure. Nonetheless, STAT3-mediated atypical IFN-? signaling appeared as a negligible factor for PD-L1 and PD-L2 expression. These negative influences of IFN-? could be alleviated by a small-molecule inhibitor of STAT3, stattic, which also inhibited the upregulation of PD-L1. In conclusion, induction of myeloid maturation enhances the responsiveness of AML and MDS cells to IFN-?. However, these malignant myeloid cells can exploit both STAT3 pathway and PD-1 ligands to survive IFN-?-mediated immunity and maintain secondary immune resistance.

SUBMITTER: Yoyen-Ermis D 

PROVIDER: S-EPMC6691003 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature