BATF is a major driver of NK cell epigenetic reprogramming and dysfunction in AML

Area of Science:

• Immunology
• Cancer Biology
• Molecular Biology

Background:

• Myelodysplastic syndrome and acute myeloid leukemia (AML) represent a spectrum of myeloid malignancies with poor outcomes in relapsed/refractory cases.
• Natural killer (NK) cells in patients with myeloid malignancies exhibit functional impairment, including reduced killing capacity and altered metabolism, at the single-cell level.
• This NK cell dysfunction is characterized by an exhausted phenotype, suggesting a need for novel therapeutic strategies.

Purpose of the Study:

• To elucidate the mechanism underlying NK cell dysfunction in AML.
• To identify key molecular players mediating the cross-talk between NK cells and myeloid blasts.
• To explore therapeutic targets for restoring NK cell function in AML.

Main Methods:

• Single-cell transcriptomic and proteomic analyses to characterize NK cell dysfunction.
• Investigation of cell-cell contact-dependent mechanisms between NK cells and myeloid blasts.
• Functional assays in vitro and in vivo to assess NK cell activity.
• Analysis of the role of the αvβ-integrin/TGF-β/SMAD pathway and BATF transcription factor.

Main Results:

• NK cell dysfunction is mediated by direct cell-cell contact with myeloid blasts.
• The αvβ-integrin/TGF-β/SMAD pathway is involved in preventing NK cell dysfunction, while epigenetic reprogramming contributes to its persistence.
• BATF was identified as a crucial transcription factor regulating NK cell exhaustion genes (HAVCR2, LAG3, TIGIT, CTLA4).
• SMAD2/3 directly regulates and induces BATF, which in turn drives NK cell exhaustion.
• BATF deletion significantly improved NK cell function against AML in vitro and in vivo.

Conclusions:

• A novel mechanism of NK cell immune evasion in AML involves epigenetic reprogramming and inactivation by myeloid blasts via BATF.
• Targeting the TGF-β pathway or BATF can prevent or reverse NK cell dysfunction.
• Allogeneic NK cell adoptive therapy, combined with strategies targeting TGF-β or BATF, holds promise for treating myeloid malignancies.