Entinostat augments NK cell functions via epigenetic upregulation of IFIT1-STING-STAT4 pathway
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John M. Idso1, Shunhua Lao1, Nathan J. Schloemer1,2, Jeffrey Knipstein2, Robert Burns3, Monica S. Thakar1,2,* and Subramaniam Malarkannan1,2,4,5,*
1 Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Versiti, Milwaukee, WI, USA
2 Division of Pediatric Hematology-Oncology-BMT, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA
3 Bioinformatics Core, Blood Research Institute, Versiti, Milwaukee, WI, USA
4 Divson of Hematology-Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
5 Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, USA
* Co-senior authors
|Monica S. Thakar,||email:||firstname.lastname@example.org|
Keywords: NK cells; histone deacetylase inhibitor; Ewing sarcoma; rhabdomyosarcoma; immunotherapy
Received: September 10, 2019 Accepted: March 03, 2020 Published: May 19, 2020
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.
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