Entinostat augments NK cell functions via epigenetic upregulation of IFIT1-STING-STAT4 pathway

Area of Science:

• Immunology
• Cancer Biology
• Pharmacology

Background:

• Histone deacetylase inhibitors (HDACi) represent a promising cancer therapy.
• The impact of HDACi on natural killer (NK) cell anti-tumor immunity is largely unknown.

Purpose of the Study:

• To investigate the effect of the HDAC inhibitor entinostat on human primary NK cells and sarcoma cell lines.
• To elucidate the underlying molecular mechanisms of entinostat's action on NK cell-mediated anti-tumor responses.

Main Methods:

• Treatment of human primary NK cells and rhabdomyosarcoma/Ewing sarcoma cell lines with entinostat.
• Analysis of NKG2D, ULBP1, HLA, and MICA/B expression.
• Assessment of NK cell cytotoxicity and interferon-gamma (IFN-γ) production.
• Chromatin accessibility assays and transcriptome analysis to identify molecular pathways.

Main Results:

• Entinostat upregulated NKG2D on NK cells and ULBP1, HLA, MICA/B on tumor cells.
• Entinostat enhanced NK cell cytotoxicity and IFN-γ production against tumor cells.
• Mechanistically, entinostat increased IFIT1 expression via enhanced chromatin accessibility, activating IRF1, STAT4, and STING pathways.

Conclusions:

• Entinostat potentiates NK cell anti-tumor activity through a novel IFIT1-STING-IRF1-STAT4 pathway.
• This mechanism enhances NK cell-mediated cytotoxicity and IFN-γ production against specific sarcoma types.
• Entinostat demonstrates potential as an immunomodulatory agent in cancer therapy.