Myeloid maturation potentiates STAT3-mediated atypical IFN-\u03b3 signaling and upregulation of PD-1 ligands in AML and MDS

Digdem Yoyen-Ermis,Tolga Sutlu,Utku Horzum,Yahya Buyukasik,Gurcan Tunali,Didem Ozkazanc,Gunes Esendagli,Ece Tavukcuoglu

doi:10.1038/s41598-019-48256-4

Digdem Yoyen-Ermis, Tolga Sutlu + Show 6 more

Open Access

https://doi.org/10.1038/s41598-019-48256-4

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Abstract

Interferon (IFN)-γ is the major mediator of anti-tumor immune responses; nevertheless, cancer cells use intrigue strategies to alter IFN-γ signaling and avoid elimination. Understanding the immune regulatory mechanisms employed by acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cells upon exposure to IFN-γ is critical for development of immunotherapy and checkpoint blockade therapy approaches. This study aims to explore the influence of myeloid maturation on IFN-γ-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 1α,25-dihydroxyvitamin D3 (vitamin D) increased the CD11b+ fraction that expressed PD-1 ligands in response to IFN-γ. Intriguingly, STAT3 pathway was potently induced by IFN-γ and strengthened upon prolonged exposure. Nonetheless, STAT3-mediated atypical IFN-γ signaling appeared as a negligible factor for PD-L1 and PD-L2 expression. These negative influences of IFN-γ 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-γ. However, these malignant myeloid cells can exploit both STAT3 pathway and PD-1 ligands to survive IFN-γ-mediated immunity and maintain secondary immune resistance.

Highlights

Regulatory failures in T-cell mediated anti-tumor immune responses, which correlate with disease progression and severity, are widely observed in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)[1,2]
Immature facets and heterogeneity of AML and MDS cells are among the major obstacles in developing successful therapy approaches[38]
Even though myeloid maturation is characterized with terminal differentiation and a reduction in proliferative capacity, the well-differentiated subtypes of myeloproliferative diseases have been associated with disease severity and worse prognosis[38,39]

Summary

Introduction

Regulatory failures in T-cell mediated anti-tumor immune responses, which correlate with disease progression and severity, are widely observed in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)[1,2]. Even though the anti-tumor activities of IFN-γ are well-acknowledged, this cytokine can initiate regulatory feedback mechanisms to avoid collateral damage and to maintain homeostasis[8,9]. Inhibitory molecules such as programmed death ligand-1 (PD-L1) and PD-L2 are upregulated in response to IFN-γ8,10–12. The present study aims to investigate PD-1 ligands’ upregulation and STAT3 activation as secondary immune resistance mechanisms elicited by AML and MDS cells upon exposure to IFN-γ under the maturation pressure by ATRA or D3 treatment. A small-molecule alleged for STAT3 inhibition, interfered both with STAT3 and STAT1 activation, and hampered IFN-γ-induced PD-L1 expression in AML or MDS

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