Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Myeloma

HDAC inhibition by LBH589 affects the phenotype and function of human myeloid dendritic cells

Leukemia volume 25, pages 161–168 (2011)Cite this article

Subjects

Abstract

LBH589 is a novel pan-histone deacetylase (HDAC) inhibitor that has potent antitumor activity in multiple myeloma and other hematological malignancies. However, its impact on the immune system has not been defined. We here evaluated the effects of LBH589 on human myeloid dendritic cells (DCs) at clinically relevant concentrations. Exposure to LBH589 affected the surface molecule expression on immature and mature DCs, which was associated with DC maturation (CD83↓), antigen presentation (human leukocyte antigen-ABC↓) and T-cell co-stimulation (CD40↓ and CD86↑). LBH589 decreased both protein and polysaccharide antigen uptake capacities by DCs. Importantly, LBH589 impaired DC function to stimulate antigen-specific immune responses, resulting in the significant reduction of invariant natural killer T-cell (CD1d-restricted) and T-cell (major histocompatibility complex-restricted) activation in innate and adaptive immunity. LBH589 also significantly repressed the production of interleukin (IL)-6, IL-10, IL-12p70, IL-23 and tumor necrosis factor-α by Toll-like receptor (TLR)3 and TLR4-induced DC activation, indicating an important role of HDAC activity in immune regulation and inflammation. RelB, a component of the nuclear factor-κ B signaling pathway, was the key component regulated by HDAC inhibition in DCs. Together, our preclinical study demonstrates that LBH589 significantly impairs the phenotype and function of DCs, indicating a need for monitoring the immune status in patients receiving HDAC inhibitor therapy. It also provides a rationale to evaluate LBH589 activity for the treatment of inflammation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Drummond DC, Noble CO, Kirpotin DB, Guo Z, Scott GK, Benz CC . Clinical development of histone deacetylase inhibitors as anticancer agents. Annu Rev Pharmacol Toxicol 2005; 45: 495–528.

    Article  CAS  PubMed  Google Scholar 

  2. Minucci S, Pelicci PG . Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 2006; 6: 38–51.

    Article  CAS  PubMed  Google Scholar 

  3. Atadja P . Development of the pan-DAC inhibitor panobinostat (LBH589): successes and challenges. Cancer Lett 2009; 280: 233–241.

    Article  CAS  PubMed  Google Scholar 

  4. Glozak MA, Seto E . Histone deacetylases and cancer. Oncogene 2007; 26: 5420–5432.

    Article  CAS  PubMed  Google Scholar 

  5. Leoni F, Zaliani A, Bertolini G, Porro G, Pagani P, Pozzi P et al. The antitumor histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits antiinflammatory properties via suppression of cytokines. Proc Natl Acad Sci USA 2002; 99: 2995–3000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Choi JH, Oh SW, Kang MS, Kwon HJ, Oh GT, Kim DY . Trichostatin A attenuates airway inflammation in mouse asthma model. Clin Exp Allergy 2005; 35: 89–96.

    Article  CAS  PubMed  Google Scholar 

  7. Camelo S, Iglesias AH, Hwang D, Due B, Ryu H, Smith K et al. Transcriptional therapy with the histone deacetylase inhibitor trichostatin A ameliorates experimental autoimmune encephalomyelitis. J Neuroimmunol 2005; 164: 10–21.

    Article  CAS  PubMed  Google Scholar 

  8. Bode KA, Schroder K, Hume DA, Ravasi T, Heeg K, Sweet MJ et al. Histone deacetylase inhibitors decrease Toll-like receptor-mediated activation of proinflammatory gene expression by impairing transcription factor recruitment. Immunology 2007; 122: 596–606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Reddy P, Sun Y, Toubai T, Duran-Struuck R, Clouthier SG, Weisiger E et al. Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase-dependent DC functions and regulates experimental graft-versus-host disease in mice. J Clin Invest 2008; 118: 2562–2573.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Scuto A, Kirschbaum M, Kowolik C, Kretzner L, Juhasz A, Atadja P et al. The novel histone deacetylase inhibitor, LBH589, induces expression of DNA damage response genes and apoptosis in Ph- acute lymphoblastic leukemia cells. Blood 2008; 111: 5093–5100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cha TL, Chuang MJ, Wu ST, Sun GH, Chang SY, Yu DS et al. Dual degradation of aurora A and B kinases by the histone deacetylase inhibitor LBH589 induces G2-M arrest and apoptosis of renal cancer cells. Clin Cancer Res 2009; 15: 840–850.

    Article  CAS  PubMed  Google Scholar 

  12. Qian DZ, Kato Y, Shabbeer S, Wei Y, Verheul HM, Salumbides B et al. Targeting tumor angiogenesis with histone deacetylase inhibitors: the hydroxamic acid derivative LBH589. Clin Cancer Res 2006; 12: 634–642.

    Article  CAS  PubMed  Google Scholar 

  13. Verheul HM, Salumbides B, Van Erp K, Hammers H, Qian DZ, Sanni T et al. Combination strategy targeting the hypoxia inducible factor-1 alpha with mammalian target of rapamycin and histone deacetylase inhibitors. Clin Cancer Res 2008; 14: 3589–3597.

    Article  CAS  PubMed  Google Scholar 

  14. Glaser KB . HDAC inhibitors: clinical update and mechanism-based potential. Biochem Pharmacol 2007; 74: 659–671.

    Article  CAS  PubMed  Google Scholar 

  15. Guermonprez P, Valladeau J, Zitvogel L, Thery C, Amigorena S . Antigen presentation and T cell stimulation by dendritic cells. Annu Rev Immunol 2002; 20: 621–667.

    Article  CAS  PubMed  Google Scholar 

  16. McKenzie BS, Kastelein RA, Cua DJ . Understanding the IL-23-IL-17 immune pathway. Trends Immunol 2006; 27: 17–23.

    Article  CAS  PubMed  Google Scholar 

  17. Brogdon JL, Xu Y, Szabo SJ, An S, Buxton F, Cohen D et al. Histone deacetylase activities are required for innate immune cell control of Th1 but not Th2 effector cell function. Blood 2007; 109: 1123–1130.

    Article  CAS  PubMed  Google Scholar 

  18. Song W, van der Vliet HJ, Tai YT, Prabhala R, Wang R, Podar K et al. Generation of antitumor invariant natural killer T cell lines in multiple myeloma and promotion of their functions via lenalidomide: a strategy for immunotherapy. Clin Cancer Res 2008; 14: 6955–6962.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Exley M, Garcia J, Balk SP, Porcelli S . Requirements for CD1d recognition by human invariant Valpha24+ CD4-CD8- T cells. J Exp Med 1997; 186: 109–120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. van der Vliet HJ, Molling JW, Nishi N, Masterson AJ, Kölgen W, Porcelli SA et al. Polarization of Valpha24+ Vbeta11+ natural killer T cells of healthy volunteers and cancer patients using alpha-galactosylceramide-loaded and environmentally instructed dendritic cells. Cancer Res 2003; 63: 4101–4106.

    CAS  PubMed  Google Scholar 

  21. Godfrey DI, Kronenberg M . Going both ways: immune regulation via CD1d-dependent NKT cells. J Clin Invest 2004; 114: 1379–1388.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lyakh L, Trinchieri G, Provezza L, Carra G, Gerosa F . Regulation of interleukin-12/interleukin-23 production and the T-helper 17 response in humans. Immunol Rev 2008; 226: 112–131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Goriely S, Neurath MF, Goldman M . How microorganisms tip the balance between interleukin-12 family members. Nat Rev Immunol 2008; 8: 81–86.

    Article  CAS  PubMed  Google Scholar 

  24. Napolitani G, Rinaldi A, Bertoni F, Sallusto F, Lanzavecchia A . Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1-polarizing program in dendritic cells. Nat Immunol 2005; 6: 769–776.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Akira S, Uematsu S, Takeuchi O . Pathogen recognition and innate immunity. Cell 2006; 124: 783–801.

    Article  CAS  PubMed  Google Scholar 

  26. Honda K, Taniguchi T . IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nat Rev Immunol 2006; 6: 644–658.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Novartis Pharmaceutical Inc. (Cambridge, MA, USA) for kindly providing LBH589. We also thank Kirin Brewery Co. Ltd. (Gunma, Japan) for kindly providing α-GalCer. This work is supported in part by the National Institutes of Health Grants P050-100707 and PO1-78378 (NCM and KCA), and a Merit Review Award from the Research Service Veterans Health Care (NCM).

Author information

Authors and Affiliations

  1. Department of M,

    W Song, Y-T Tai, Z Tian, T Hideshima, D Chauhan, P Nanjappa, K C Anderson & N C Munshi

  2. edical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    W Song, Y-T Tai, Z Tian, T Hideshima, D Chauhan, P Nanjappa, K C Anderson & N C Munshi

  3. Hematology/Oncology Division, Department of Medicine, Cancer Biology Program, Beth Israel-Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    M A Exley

  4. Veterans Administration (VA) Boston Health Care System, Harvard Medical School, Boston, MA, USA

    N C Munshi

Authors
  1. W Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y-T Tai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Z Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T Hideshima
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D Chauhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. P Nanjappa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M A Exley
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. K C Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. N C Munshi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to N C Munshi.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Song, W., Tai, YT., Tian, Z. et al. HDAC inhibition by LBH589 affects the phenotype and function of human myeloid dendritic cells. Leukemia 25, 161–168 (2011). https://doi.org/10.1038/leu.2010.244

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2010.244

Keywords

This article is cited by

Search

Advanced search

Quick links