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Multiple myeloma, gammopathies

Histone deacetylase (HDAC) inhibitor ACY241 enhances anti-tumor activities of antigen-specific central memory cytotoxic T lymphocytes against multiple myeloma and solid tumors

Abstract

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-DRLow/-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 XBP1unspliced184–192 (YISPWILAV) and XBP1spliced367–375 (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.

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Acknowledgements

The authors acknowledge Mr. John Daley and Ms. Suzan Lazo-Kallanian from the flow cytometry facility at Dana-Farber Cancer Institute for providing flow cytometry assistance. This work was supported in part by grants from the National Institutes of Health Grants RO1-124929 to Dr. Nikhil C. Munshi, P50-100007, PO1-78378 and PO1-155258 to Drs. Kenneth C. Anderson and Nikhil C. Munshi, and RO1-50947 to Dr. Kenneth C. Anderson. Dr. Kenneth C. Anderson is an American Cancer Society Clinical Research Professor.

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Correspondence to Jooeun Bae.

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N.C. Munshi is on advisory board of Celgene, Millennium and Novartis; K.C. Anderson is on advisory board of Gilead, Millennium and Bristol Myers Squibb; and P.G. Richardson is on advisory board of Celgene, Millennium and Johnson & Johnson. N.C. Munshi, K.C. Anderson and J. Bae have ownership interest and are advisory board members in OncoPep Inc. The remaining authors declare that they have no conflict of interest.

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Bae, J., Hideshima, T., Tai, YT. et al. Histone deacetylase (HDAC) inhibitor ACY241 enhances anti-tumor activities of antigen-specific central memory cytotoxic T lymphocytes against multiple myeloma and solid tumors. Leukemia 32, 1932–1947 (2018). https://doi.org/10.1038/s41375-018-0062-8

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