Histone deacetylase inhibitors sensitize tumour cells for cytotoxic effects of natural killer cells.
Histone deacetylase inhibitors (HDIs) are emerging as potent anti-tumour agents which induce cell cycle arrest, differentiation and/or apoptosis in many tumour cells. Furthermore, they render tumour cells more sensitive to other therapeutic regimens like ionizing radiation, chemotherapy and recombinant tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). Here, we show that the HDIs suberoylanilide hydroxamic acid (SAHA; vorinostat), sodium butyrate (NaB) and MS-275 sensitized DAOY and PC3 tumour cells for the cytotoxic effects of IL-2-activated PBMCs. In (51)Cr-release assays, blockade of the activating NK receptors DNAM-1, NKG2D and the NCRs completely abrogated tumour cell lysis, revealing that NK cells were the main effector cells involved. HDIs increased the tumour surface expression of ligands for the activating NK receptors NKG2D and DNAM-1 thereby facilitating tumour cell recognition by NK cells. These results suggest that the combination of HDIs and immunotherapy may be an effective strategy for anti-cancer therapy.
Schmudde
Mareike
M
Institut für Immunologie und Transfusionsmedizin, [corrected] Ernst-Moritz-Arndt-Universität Greifswald, Ferdinand-Sauerbruch-Str., D-17487 Greifswald, Germany. mareike.schmudde@uni-greifswald.de
Braun
André
A
Pende
Daniela
D
Sonnemann
Jürgen
J
Klier
Ulrike
U
Beck
James F
JF
Moretta
Lorenzo
L
Bröker
Barbara M
BM
D000970:Antineoplastic Agents / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D052118:Lysosomal-Associated Membrane Protein 1 / Q000187:drug effects / Q000276:immunology; D008297:Male; D011471:Prostatic Neoplasms / Q000276:immunology / Q000473:pathology; D014750:Vincristine / Q000494:pharmacology; D000077337:Vorinostat
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D052118:Lysosomal-Associated Membrane Protein 1; D000077337:Vorinostat; D014750:Vincristine