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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Change history
15 April 2024
A Correction to this paper has been published: https://doi.org/10.1038/s41375-024-02185-y
References
Topalian SL, Taube JM, Anders RA, Pardoll DM. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer. 2016;16:275–87.
Martin K, Schreiner J, Zippelius A. Modulation of APC function and anti-tumor immunity by anti-cancer drugs. Front Immunol. 2015;6:501.
Kersten K, Salvagno C, de Visser KE. Exploiting the immunomodulatory properties of chemotherapeutic drugs to improve the success of cancer immunotherapy. Front Immunol. 2015;6:516.
Kroesen M, Gielen P, Brok IC, Armandari I, Hoogerbrugge PM, Adema GJ. HDAC inhibitors and immunotherapy; a double edged sword? Oncotarget. 2014;5:6558–72.
Cicek MS, Koestler DC, Fridley BL, Kalli KR, Armasu SM, Larson MC, et al. Epigenome-wide ovarian cancer analysis identifies a methylation profile differentiating clear-cell histology with epigenetic silencing of the HERG K + channel. Hum Mol Genet. 2013;22:3038–47.
Akhtar-Zaidi B, Cowper-Sal-lari R, Corradin O, Saiakhova A, Bartels CF, Balasubramanian D, et al. Epigenomic enhancer profiling defines a signature of colon cancer. Science. 2012;336:736–9.
You JS, Jones PA. Cancer genetics and epigenetics: two sides of the same coin? Cancer Cell. 2012;22:9–20.
Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis. 2010;31:27–36.
Maolanon AR, Madsen AS, Olsen CA. Innovative strategies for selective inhibition of histone deacetylases. Cell Chem Biol. 2016;23:759–68.
Batchu SN, Brijmohan AS, Advani A. The therapeutic hope for HDAC6 inhibitors in malignancy and chronic disease. Clin Sci (Lond). 2016;130:987–1003.
Hideshima T, Mazitschek R, Qi J, Mimura N, Tseng J-C, Kung AL, Bradner JE, et al. HDAC 6 inhibitor WT 161 downregulates growth factor receptors in breast cancer. Oncotarget. 2017;8:80109–23. in press
Hideshima T, Qi J, Paranal RM, Tang W, Greenberg E, West N, et al. Discovery of selective small-molecule HDAC6 inhibitor for overcoming proteasome inhibitor resistance in multiple myeloma. Proc Natl Acad Sci USA. 2016;113:13162–7.
Villagra A, Cheng F, Wang HW, Suarez I, Glozak M, Maurin M, et al. The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance. Nat Immunol. 2009;10:92–100.
Leoni F, Fossati G, Lewis EC, Lee JK, Porro G, Pagani P, et al. The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo. Mol Med. 2005;11:1–15.
Vogl DT, Raje N, Jagannath S, Richardson P, Hari P, Orlowski R, et al. Ricolinostat, the first selective histone deacetylase 6 inhibitor, in combination with bortezomib and dexamethasone for relapsed or refractory multiple myeloma. Clin Cancer Res. 2017;23:3307–15.
Yee AJ, Bensinger WI, Supko JG, Voorhees PM, Berdeja JG, Richardson PG, et al. Ricolinostat plus lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: a multicentre phase 1b trial. Lancet Oncol. 2016;17:1569–78.
Mishima Y, Santo L, Eda H, Cirstea D, Nemani N, Yee AJ, et al. Ricolinostat (ACY-1215) induced inhibition of aggresome formation accelerates carfilzomib-induced multiple myeloma cell death. Br J Haematol. 2015;169:423–34.
Santo L, Hideshima T, Kung AL, Tseng JC, Tamang D, Yang M, et al. Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood. 2012;119:2579–89.
Ray A, Das DS, Song Y, Hideshima T, Chauhan D, Anderson KC Combination of a novel HDAC6 inhibitor ACY-241 and anti-PD-L1 antibody enhances anti-tumor immunity and cytotoxicity in multiple myeloma. Leukemia 2017 https://doi.org/10.1038/leu.2017.322.
Rogel A, Willoughby JE, Buchan SL, Leonard HJ, Thirdborough SM, Al-Shamkhani A. Akt signaling is critical for memory CD8 + T-cell development and tumor immune surveillance. Proc Natl Acad Sci USA. 2017;114:E1178–87.
Araki K, Morita M, Bederman AG, Konieczny BT, Kissick HT, Sonenberg N, Ahmed R. Translation is actively regulated during the differentiation of CD8 + effector T cells. Nat Immunol. 2017;18:1046–57.
Crotty S, Johnston RJ, Schoenberger SP. Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Nat Immunol. 2010;11:114–20.
Knudson KM, Pritzl CJ, Saxena V, Altman A, Daniels MA, Teixeiro E. NFκB-Pim-1-Eomesoderminaxis is critical for maintaining CD8 T-cell memory quality. Proc Natl Acad Sci USA. 2017;114:E1659–67.
Gnanaprakasam JNR, Sherman JW, Wang R. MYC and HIF in shaping immune response and immune metabolism. Cytokine Growth Factor Rev. 2017;35:63–70.
Larbi A, Zelba H, Goldeck D, Pawelec G. Induction of HIF-1alpha and the glycolytic pathway alters apoptotic and differentiation profiles of activated human T cells. J Leukoc Biol. 2010;87:265–73.
Li G, Yang Q, Zhu Y, Wang HR, Chen X, Zhang X, et al. T-Bet and eomes regulate the balance between the effector/central memory T cells versus memory stem like T cells. PLoS One. 2013;8:e67401.
Bae J, Prabhala R, Voskertchian A, Brown A, Maguire C, Richardson P, et al. A multiepitope of XBP1, CD138 and CS1 peptides induces myeloma-specific cytotoxic T lymphocytes in T cells of smoldering myeloma patients. Leukemia. 2015;29:218–29.
Bae J, Samur M, Munshi A, Hideshima T, Keskin D, Kimmelman A, et al. Heteroclitic XBP1 peptides evoke tumor-specific memory cytotoxic T lymphocytes against breast cancer, colon cancer, and pancreatic cancer cells. OncoImmunology. 2014;3:e970914.
Bae J, Smith R, Daley J, Mimura N, Tai YT, Anderson KC, et al. Myeloma-specific multiple peptides able to generate cytotoxic T lymphocytes: a potential therapeutic application in multiple myeloma and other plasma cell disorders. Clin Cancer Res. 2012;18:4850–60.
Bae J, Carrasco R, Lee AH, Prabhala R, Tai YT, Anderson KC, et al. Identification of novel myeloma-specific XBP1 peptides able to generate cytotoxic T lymphocytes: a potential therapeutic application in multiple myeloma. Leukemia. 2011;25:1610–9.
Murakami T, Sato A, Chun NA, Hara M, Naito Y, Kobayashi Y, et al. Transcriptional modulation using HDACi depsipeptide promotes immune cell-mediated tumor destruction of murine B16 melanoma. J Invest Dermatol. 2008;128:1506–16.
Roulois D, Blanquart C, Panterne C, Gueugnon F, Gregoire M, Fonteneau JF. Downregulation of MUC1 expression and its recognition by CD8(+) T cells on the surface of malignant pleural mesothelioma cells treated with HDACi. Eur J Immunol. 2012;42:783–9.
Zhang Q, Zhang L, Li L, Wang Z, Ying J, Fan Y, et al. Interferon regulatory factor 8 functions as a tumor suppressor in renal cell carcinoma and its promoter methylation is associated with patient poor prognosis. Cancer Lett. 2014;354:227–34.
Woods DM, Woan K, Cheng F, Wang H, Perez-Villarroel P, Lee C, et al. The antimelanoma activity of the histone deacetylase inhibitor panobinostat (LBH589) is mediated by direct tumor cytotoxicity and increased tumor immunogenicity. Melanoma Res. 2013;23:341–8.
Khan AN, Gregorie CJ, Tomasi TB. Histone deacetylase inhibitors induce TAP, LMP, Tapasin genes and MHC class I antigen presentation by melanoma cells. Cancer Immunol Immunother. 2008;57:647–54.
Magner WJ, Kazim AL, Stewart C, Romano MA, Catalano G, Grande C, et al. Activation of MHC class I, II, and CD40 gene expression by histone deacetylase inhibitors. J Immunol. 2000;165:7017–24.
Araki K, Turner AP, Shaffer VO, Gangappa S, Keller SA, Bachmann MF, et al. mTOR regulates memory CD8 T-cell differentiation. Nature . 2009;460:108–12.
Kerdiles YM, Beisner DR, Tinoco R, Dejean AS, Castrillon DH, DePinho RA, et al. Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor. Nat Immunol. 2009;10:176–84.
Pollizzi KN, Patel CH, Sun IH, Oh MH, Waickman AT, Wen J, et al. mTORC1 and mTORC2 selectively regulate CD8+ T cell differentiation. J Clin Invest. 2015;125:2090–108.
Rao RR, Li Q, Shrikant PA. Fine-tuning CD8(+) T cell functional responses: mTOR acts as a rheostat for regulating CD8(+) T cell proliferation, survival and differentiation? Cell Cycle. 2010;9:2996–3001.
Nanjappa SG, Hernández-Santos N, Galles K, Wüthrich M, Suresh M, Klein BS. Intrinsic MyD88-Akt1-mTOR signaling coordinates disparate Tc17 and Tc1 responses during vaccine immunity against fungal pneumonia. PLoS Pathog. 2015;11:e1005161.
Veliça P, Zech M, Henson S, Holler A, Manzo T, Pike R, et al. Genetic regulation of fate decisions in therapeutic T cells to enhance tumor protection and memory formation. Cancer Res. 2015;75:2641–52.
Cheng J, Hamilton KS, Kane LP. Phosphorylation of Carma1, but not Bcl10, by Akt regulates TCR/CD28-mediated NF-κB induction and cytokine production. Mol Immunol. 2014;59:110–6.
Kane LP, Andres PG, Howland KC, Abbas AK, Weiss A. Akt provides the CD28 costimulatory signal for up-regulation of IL-2 and IFN-gamma but not TH2 cytokines. Nat Immunol. 2001;2:37–44.
Bae J, Keskin D, Cowens K, Lee AH, Dranoff G, Munshi NC, et al. Lenalidomide polarizes Th1-specific anti-rumor immune response and expands XBP1 antigen-specific central memory CD3+CD8+ T cells against various solid tumors. J Leuk. 2015;3:178–90.
Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997;91:231–41.
Cantley LC, Neel BG. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci USA. 1999;96:4240–5.
Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, et al. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell. 2006;11:859–71.
Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124:471–84.
Liu P, Begley M, Michowski W, Inuzuka H, Ginzberg M, Gao D, et al. Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus. Nature. 2014;508:541–5.
Zeng H, Chi H. mTOR signaling and transcriptional regulation in T lymphocytes. Transcription. 2014;5:e28263.
Rao RR, Li Q, Gubbels Bupp MR, Shrikant PA. Transcription factor Foxo1 represses T-bet-mediated effector functions and promotes memory CD8(+) T cell differentiation. Immunity. 2012;36:374–87.
Glimcher LH, Townsend MJ, Sullivan BM, Lord GM. Recent developments in the transcriptional regulation of cytolytic effector cells. Nat Rev Immunol. 2004;4:900–11.
Pearce EL, Mullen AC, Martins GA, Krawczyk CM, Hutchins AS, Zediak VP, et al. Control of effector CD8+ T cell function by the transcription factor Eomesodermin. Science. 2003;302:1041–3.
Li G, Yang Q, Zhu Y, Wang HR, Chen X, Zhang X, et al. T-bet and Eomes regulate the balance between the effector/central memory T cells versus memory stem like T cells. PLoS One. 2013;8:e67401.
Pipkin M, Sacks J, Cruz-Guilloty F, Lichtenheld M, Bevan M, Rao A. Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells. Immunity. 2010;32:79–90.
Chen LJ, Zheng X, Shen YP, Zhu YB, Li Q, Chen J, et al. Higher numbers of T-bet(+) intratumoral lymphoid cells correlate with better survival in gastric cancer. Cancer Immunol Immunother. 2012;62:553–61.
Liu Z, Liu JQ, Talebian F, Wu LC, Li S, Bai XF. IL-27 enhances the survival of tumor antigen-specific CD8 + T cells and programs them into IL-10-producing, memory precursor-like effector cells. Eur J Immunol. 2013;4:468–79.
Crotty S, Johnston RJ, Schoenberger SP. Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Nat Immunol. 2010;11:114–20.
D’Cruz LM, Rubinstein MP, Goldrath AW. Surviving the crash: transitioning from effector to memory CD8+ T cell. Semin Immunol. 2009;21:92–98.
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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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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DOI: https://doi.org/10.1038/s41375-018-0062-8
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