Oncotarget: Entinostat augments NK cell functions via epigenetic upregulation

Volume 11, Issue 20 of @Oncotarget reported that the authors evaluated the impact of a benzamide HDACi, entinostat, on human primary NK cells as well as tumor cell lines.

Additionally, entinostat increased both cytotoxicity and IFN- production in human NK cells following coculture with these tumor cells.

Dr. Monica S. Thakar from The Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Versiti and The Division of Pediatric Hematology-Oncology-BMT, Department of Pediatrics at The Medical College of Wisconsin as well as Dr. Subramaniam Malarkannan also from The Malarkannan Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Versiti and The Division of Pediatric Hematology-Oncology-BMT, Department of Pediatrics at The Medical College of Wisconsin but also affiliated with The Division of Hematology-Oncology, Department of Medicine at The Medical College of Wisconsin and The Department of Microbiology and Immunology at The Medical College of Wisconsin agreed together, "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."

"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"

- Dr. Monica S. Thakar, The Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Versiti and The Division of Pediatric Hematology-Oncology-BMT, Department of Pediatrics at The Medical College of Wisconsin & Dr. Subramaniam Malarkannan The Malarkannan Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Versiti and The Division of Pediatric Hematology-Oncology-BMT, Department of Pediatrics at The Medical College of Wisconsin and affiliated with The Division of Hematology-Oncology, Department of Medicine at The Medical College of Wisconsin and The Department of Microbiology and Immunology at The Medical College of Wisconsin

NK cells are the major lymphocytes of the innate immune system and play an essential role in tumor clearance.

NK cells are of particular importance in the context of hematopoietic cell transplant as they are the first cell type to recover following engraftment of donor stem cells.

They hypothesize that overcoming tumor microenvironment-mediated tolerance in the epigenome of the NK cell can increase tumor clearance.

Figure 1: Entinostat upregulates the expression of activating and inhibitory human NK cell receptors. (A) Effect of entinostat on NK cell-activating receptors, including DNAM, NKp46, NKG2D, and NKp80. The total percent receptor-positive of the CD3ε⁻CD56⁺ NK cells and their Mean Fluorescent Intensity (MFI) normalized to DMSO control are shown. (B) Effect of entinostat on NK cell inhibitory receptors including NKG2A, PD-1, KIR2DL1, KIR2DL2, KIR2DS4, KIR2DL5, and KIR3DL1. Data are shown as percent receptor-positive of the CD3ε⁻CD56⁺ NK cells and their MFI normalized to DMSO control are shown. Data shown in A and B are obtained by treating purified NK cells with or without entinostat from five to seven healthy donors per group. Data presented are the mean ± SD. Statistical significance was calculated using a ratio paired t-test. ^*p < 005; ^**p < 0.01.

Coculture of NK cells and tumors demonstrated an increase in both cytotoxic degranulation and IFN- production in NK cells.

Collectively, their results provide a novel mechanism of action of entinostat-regulated NK cell effector functions and identify targets that could help augment NK cell-mediated anti-tumor responses.

The Thakar/Malarkannan Research Team concluded in their Oncotarget Research Article that historically, methods to activate NK cells in vivo have been effective, but have also induced toxic side effects in patients.

Their results confirm its effectiveness as both an inducer of NK effector functions, but also as an approach to make solid tumors more visible to the immune system by increasing tumor antigen expression.

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DOI - https://doi.org/10.18632/oncotarget.27546

Full text - https://www.oncotarget.com/article/27546/text/

Correspondence to - Monica S. Thakar - msthakar@fredhutch.org and Subramaniam Malarkannan - smalarkannan@versiti.org

Keywords - NK cells, histone deacetylase inhibitor, Ewing sarcoma, rhabdomyosarcoma, immunotherapy

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