Myeloid maturation potentiates STAT3-mediated atypical IFN-gamma signaling and upregulation of PD-1 ligands in AML and MDS
Date
2019Author
Yoyen-Ermis, Digdem and Tunali, Gurcan and Tavukcuoglu, Ece and Horzum,
Utku and Ozkazanc, Didem and Sutlu, Tolga and Buyukasik, Yahya and
Esendagli, Gunes
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Show full item recordAbstract
Interferon (IFN)-gamma is the major mediator of anti-tumor immune
responses; nevertheless, cancer cells use intrigue strategies to alter
IFN-gamma signaling and avoid elimination. Understanding the immune
regulatory mechanisms employed by acute myeloid leukemia (AML) and
myelodysplastic syndrome (MDS) cells upon exposure to IFN-gamma is
critical for development of immunotherapy and checkpoint blockade
therapy approaches. This study aims to explore the influence of myeloid
maturation on IFN-gamma-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 alpha,25-dihydroxyvitamin D3 (vitamin D) increased the
CD11b(+) fraction that expressed PD-1 ligands in response to IFN-gamma.
Intriguingly, STAT3 pathway was potently induced by IFN-gamma and
strengthened upon prolonged exposure. Nonetheless, STAT3-mediated
atypical IFN-gamma signaling appeared as a negligible factor for PD-L1
and PD-L2 expression. These negative influences of IFN-gamma 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-gamma. However, these malignant myeloid cells can exploit both STAT3
pathway and PD-1 ligands to survive IFN-gamma-mediated immunity and
maintain secondary immune resistance.
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