Leukemia, 2018-09, Vol.32 (9), p.1932-1947
2018
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- Autor(en) / Beteiligte
- Titel
- Histone deacetylase (HDAC) inhibitor ACY241 enhances anti-tumor activities of antigen-specific central memory cytotoxic T lymphocytes against multiple myeloma and solid tumors
- Ist Teil von
- Leukemia, 2018-09, Vol.32 (9), p.1932-1947
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2018
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Histone deacetylases (HDAC) are therapeutic targets in multiple cancers. ACY241, an HDAC6 selective inhibitor, has shown anti-multiple myeloma (MM) activity in combination with immunomodulatory drugs and proteasome inhibitors. Here we show ACY241 significantly reduces the frequency of CD138 MM cells, CD4 CD25 FoxP3 regulatory T cells, and HLA-DR CD11b CD33 myeloid-derived suppressor cells; and decreases expression of PD1/PD-L1 on CD8 T cells and of immune checkpoints in bone marrow cells from myeloma patients. ACY241 increased B7 (CD80, CD86) and MHC (Class I, Class II) expression on tumor and dendritic cells. We further evaluated the effect of ACY241 on antigen-specific cytotoxic T lymphocytes (CTL) generated with heteroclitic XBP1unspliced (YISPWILAV) and XBP1spliced (YLFPQLISV) peptides. ACY241 induces co-stimulatory (CD28, 41BB, CD40L, OX40) and activation (CD38) molecule expression in a dose- and time-dependent manner, and anti-tumor activities, evidenced by increased perforin/CD107a expression, IFN-γ/IL-2/TNF-α production, and antigen-specific central memory CTL. These effects of ACY241 on antigen-specific memory T cells were associated with activation of downstream AKT/mTOR/p65 pathways and upregulation of transcription regulators including Bcl-6, Eomes, HIF-1 and T-bet. These studies therefore demonstrate mechanisms whereby ACY241 augments immune response, providing the rationale for its use, alone and in combination, to restore host anti-tumor immunity and improve patient outcome.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0887-6924eISSN: 1476-5551DOI: 10.1038/s41375-018-0062-8Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6537609
- Format
- –
- Schlagworte
- AKT protein, Anticancer properties, Antigens, Antigens, Neoplasm - genetics, Antigens, Neoplasm - immunology, Antitumor agents, B7 antigen, Bcl-6 protein, Biomarkers, Bone marrow, Cancer, Care and treatment, CD11b antigen, CD25 antigen, CD28 antigen, CD38 antigen, CD4 antigen, CD40L protein, CD8 antigen, CD80 antigen, CD86 antigen, Cell activation, Cell Line, Tumor, Cytotoxicity, Cytotoxicity, Immunologic - drug effects, Dendritic cells, Development and progression, Drug development, Enzyme regulation, Epitopes, T-Lymphocyte - genetics, Epitopes, T-Lymphocyte - immunology, Foxp3 protein, Gene Expression Regulation, Neoplastic - drug effects, Genetic aspects, Health aspects, Histone deacetylase, Histone Deacetylase Inhibitors - pharmacology, Histone Deacetylases - metabolism, Histones, Humans, Hydrolases, Immune checkpoint, Immune response, Immune system, Immunity, Immunologic Memory, Immunological memory, Immunomodulation, Immunoregulation, Inhibitors, Interleukin 2, Lymphocyte Activation - drug effects, Lymphocyte Activation - immunology, Lymphocytes, Lymphocytes T, Major histocompatibility complex, Multiple myeloma, Multiple Myeloma - drug therapy, Multiple Myeloma - genetics, Multiple Myeloma - immunology, Multiple Myeloma - metabolism, Neoplasms - drug therapy, Neoplasms - genetics, Neoplasms - immunology, Neoplasms - metabolism, PD-1 protein, PD-L1 protein, Peptides, Peptides - immunology, Perforin, Proteasomes, Regulators, Signal Transduction - drug effects, T cells, T-Lymphocyte Subsets - drug effects, T-Lymphocyte Subsets - immunology, T-Lymphocyte Subsets - metabolism, T-Lymphocytes, Cytotoxic - drug effects, T-Lymphocytes, Cytotoxic - immunology, T-Lymphocytes, Cytotoxic - metabolism, Time dependence, Transcription, Tumors, X-Box Binding Protein 1 - chemistry, X-Box Binding Protein 1 - genetics, X-Box Binding Protein 1 - immunology, γ-Interferon