Synergistic Tumor Cytolysis by NK Cells in Combination With a Pan-HDAC Inhibitor, Panobinostat

Histone deacetylases (HDAC) are frequently overexpressed in tumors, and their inhibition has shown promising anti-tumor effects. However, the synergistic effects of HDAC inhibition with immune cell therapy have not been fully explored. Natural killer (NK) cells are cytotoxic lymphocytes for anti-tum...

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Bibliographic Details
Published in:Frontiers in immunology 2021-08, Vol.12, p.701671
Main Authors: Afolabi, Lukman O, Bi, Jiacheng, Li, Xuguang, Adeshakin, Adeleye O, Adeshakin, Funmilayo O, Wu, Haisi, Yan, Dehong, Chen, Liang, Wan, Xiaochun
Format: Article
Language:English
Subjects:
Animals
anti-PD-L1 therapy
Antineoplastic Agents - pharmacology
Cell Adhesion - drug effects
Cell Line
Cell Line, Tumor
chemotherapy
cytotoxicity
Drug Synergism
HDAC
HeLa Cells
Hep G2 Cells
Histone Deacetylase Inhibitors - pharmacology
Humans
Immunologic Surveillance - drug effects
Immunology
immunomodulator
Immunotherapy - methods
Killer Cells, Natural - drug effects
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Molecular Targeted Therapy - methods
natural killer cells
Panobinostat - pharmacology
Tight Junctions - drug effects
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Summary:Histone deacetylases (HDAC) are frequently overexpressed in tumors, and their inhibition has shown promising anti-tumor effects. However, the synergistic effects of HDAC inhibition with immune cell therapy have not been fully explored. Natural killer (NK) cells are cytotoxic lymphocytes for anti-tumor immune surveillance, with immunotherapy potential. We showed that a pan-HDAC inhibitor, panobinostat, alone demonstrated anti-tumor and anti-proliferative activities on all tested tumors . Additionally, panobinostat co-treatment or pretreatment synergized with NK cells to mediate tumor cell cytolysis. Mechanistically, panobinostat treatment increased the expression of cell adhesion and tight junction-related genes, promoted conjugation formation between NK and tumor cells, and modulates NK cell-activating receptors and ligands on tumor cells, contributing to the increased tumor cytolysis. Finally, panobinostat therapy led to better tumor control and synergized with anti-PD-L1 therapy. Our data highlights the anti-tumor potential of HDAC inhibition through tumor-intrinsic toxicity and enhancement of NK -based immunotherapy.
ISSN:1664-3224
1664-3224
DOI:10.3389/fimmu.2021.701671