Abstract
Histone deacetylase inhibitors (HDACi) are an emerging cancer therapy; however, their effect on natural killer (NK) cell-mediated anti-tumor responses remain unknown. Here, we evaluated the impact of a benzamide HDACi, entinostat, on human primary NK cells as well as tumor cell lines. Entinostat significantly upregulated the expression of NKG2D, an essential NK cell activating receptor. Independently, entinostat augmented the expression of ULBP1, HLA, and MICA/B on both rhabdomyosarcoma and Ewing sarcoma cell lines. Additionally, entinostat increased both cytotoxicity and IFN-γ production in human NK cells following coculture with these tumor cells. Mechanistically, entinostat treatment resulted in increased chromatin accessibility to the promoter region for interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) gene and thereby increasing the transcript and protein levels of IFIT1 that augmented the IFIT1-mediated IRF1, STAT4, and STING pathways. Corresponding transcriptome analysis revealed enrichment of IRF1 and STAT4 and gene sets responsible for NK cell-mediated IFN-γ production and cytotoxicity, respectively. Our results show a novel mechanism by which entinostat initiates an IFIT1-STING-mediated potentiation of STAT4 via IRF1 to augment NK cell-mediated anti-tumor responses.
Highlights
Histone deacetylase inhibitors (HDACi) represent an essential class of antineoplastic medications due to their ability to restore the function of proteins that reverse the growth and progression of a wide array of cancers with relatively minimal toxicities [1, 2]
Our results show a novel mechanism by which entinostat initiates an interferon-induced protein with tetratricopeptide repeats 1 (IFIT1)-STINGmediated potentiation of Signal Transducer and Activator of Transcription 4 (STAT4) via IRF1 to augment natural killer (NK) cell-mediated anti-tumor responses
We identify the enrichment of a gene set associated with transcription factors interferon regulatory factor-1 (IRF1) and signal transducer and activator of transcription 4 (STAT4) in NK cells following treatment with entinostat
Summary
Histone deacetylase inhibitors (HDACi) represent an essential class of antineoplastic medications due to their ability to restore the function of proteins that reverse the growth and progression of a wide array of cancers with relatively minimal toxicities [1, 2]. HDACi is used alone or in combination with other chemotherapeutic agents for a variety of pediatric and adult malignancies, including rhabdomyosarcoma and cutaneous T cell lymphoma [1, 3]. Their emerging clinical potential has led to the evaluation of HDACi for tumor treatment of several cancer types in various trials [4]. Earlier studies primarily focused on the effect of HDACi on tumor cells, while a few evaluate their impact on the immune system [5,6,7,8,9,10,11,12]. The effect of HDACi on natural killer (NK) cells has yet to be fully defined
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