Abstract
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 in vitro. 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.
Highlights
Natural killer (NK) cells are cytotoxic components of the innate immune system and are the first line of host anti-tumor immune surveillance [1]
Nanomolecular concentration of panobinostat was sufficient to initiate apoptosis in A375 cells (Figure 1A), and the number of apoptotic cells increased in a dose-dependent manner compared with vehicle-treated control
3.1.1 Low Doses of Histone deacetylase inhibitors (HDACi) (Panobinostat) Had Minimal Effect on Natural Killer (NK) and Normal Human Cell Lines Cell Viability We further evaluated the effect of panobinostat treatment on NK (YTS) cells, four normal human cell lines, and human primary NK cells viability
Summary
Natural killer (NK) cells are cytotoxic components of the innate immune system and are the first line of host anti-tumor immune surveillance [1]. Aside from being an early IFN-g producer [2], the cytolytic effector activity of NK cells is an important factor that inversely correlates with tumor incidence [3]. The cytolytic activity of NK cells depends on the recognition and release of perforin and granzymes into tumor cells [4,5,6]. Recent studies on NK cell adoptive transfer therapy and NK cell checkpoint blockade have shed light on the potential of NK–based immunotherapy [7,8,9,10], whose potentials, have not been fully exploited. Synergistic Tumor Cytolysis by NK Cells and Panobinostat Studies have shown that pretreatment of tumor cells with reagents could facilitate tumor cell lysis by NK cells [11,12,13,14], suggesting that tumor cells develop intrinsic mechanisms that could resist their cytolysis by NK cells.
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