Regulation of the expression of MHC class I-related chain A, B (MICA, MICB) via chromatin remodeling and its impact on the susceptibility of leukemic cells to the cytotoxicity of NKG2D-expressing cells.
Innate immune cells such as natural killer (NK) cells play a crucial role in antitumor immune responses. NKG2D is a major activating immunoreceptor expressed in not only NK cells but also CD8+ T cells and shows cytotoxicity against tumors by recognizing its ligands major histocompatibility complex class I-related chain A and B (MICA and MICB) on tumor cells. Recently, it has been suggested that NKG2D-mediated cytotoxicity correlates with the expression levels of NKG2D ligands on target cells. In this study, we were able to increase the expression levels of MICA and MICB on leukemic cell lines and patients' leukemic cells by treatment with trichostatin A (TsA), a histone deacetylase (HDAC) inhibitor. Chromatin immunoprecipitation (ChIP) assays revealed that treatment with TsA resulted in increased acetylation of histone H3 and decreased association with HDAC1 at the promoters of MICA and MICB. Intriguingly, upregulation of MICA and MICB by treatment with TsA led to enhancement of the susceptibility of leukemic cells to the cytotoxicity of NKG2D-expressing cells. Our results suggest that regulation of the expression of NKG2D ligands by treatment with chromatin-remodeling drugs may be an attractive strategy for immunotherapy.
Kato
N
N
Department of Hematology and Oncology, Hokkaido University, Graduate School of Medicine, Sapporo, Japan.
Tanaka
J
J
Sugita
J
J
Toubai
T
T
Miura
Y
Y
Ibata
M
M
Syono
Y
Y
Ota
S
S
Kondo
T
T
Asaka
M
M
Imamura
M
M
D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D005805:Genes, MHC Class I; D020022:Genetic Predisposition to Disease; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D019169:Jurkat Cells; D020014:K562 Cells; D008297:Male; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000378:metabolism; D055607:Receptors, Natural Killer Cell
D015395:Histocompatibility Antigens Class I; D006657:Histones; D006877:Hydroxamic Acids; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; C098080:MICB antigen; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011500:Protein Synthesis Inhibitors; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; C012589:trichostatin A