Skip to main content
SpringerLink
Log in

Inhibition of HSPs for Enhanced Immunity

  • Chapter
  • First Online:
Heat Shock Proteins in the Immune System

  • 728 Accesses

Abstract

Heat shock proteins (HSPs) are highly abundant proteins found in all cell types in the body, where they comprise approximately 1–2% of the cellular proteome. Due to the physiologically stressful conditions of the progressive tumor microenvironment (TME, i.e., hypoxia, acidosis, and high interstitial fluid pressure), expression of HSPs in tumor cells can be increased by a factor of two- to tenfold over that found in normal cells. Larger HSPs (HSP70 and HSP90) maintain the structural integrity of a broad range of tumor client proteins associated with oncogenesis and disease progression. HSPs can also be translocated to the tumor cell surface or shed into the extracellular space where they have recently been found to serve as “chaperokines” capable of modulating the function of antigen-presenting cells and immune effector cells. This chapter will provide a summary of the pleiotropic impact of HSPs on tumor immunity and suggest strategies by which HSP inhibitors (HSPi) might be best applied to optimize the antitumor efficacy of combination immunotherapy approaches.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Calderwood SK (2012) HSF1, a versatile factor in tumorogenesis. Curr Mol Med 12:1102–1107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ciocca DR, Calderwood SK (2005) Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones 10:86–103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Franceschelli S, Rosati A, Lerose R, De Nicola S, Turco MC, Pascale M (2008) Bag3 gene expression is regulated by heat shock factor 1. J Cell Physiol 215:575–577. https://doi.org/10.1002/jcp.21397

    Article  CAS  PubMed  Google Scholar 

  4. Garrido C, Brunet M, Didelot C, Zermati Y, Schmitt E, Kroemer G (2006) Heat shock proteins 27 and 70: anti-apoptotic proteins with tumorigenic properties. Cell Cycle 5:2592–2601

    Article  CAS  PubMed  Google Scholar 

  5. Ischia J, So AI (2013) The role of heat shock proteins in bladder cancer. Nat Rev Urol 10:386–395. https://doi.org/10.1038/nrurol.2013.108

    Article  CAS  PubMed  Google Scholar 

  6. Jäättelä M (1999) Heat shock proteins as cellular lifeguards. Ann Med 31:261–271

    Article  PubMed  Google Scholar 

  7. Jiang S, Tu K, Fu Q, Schmitt DC, Zhou L, Lu N et al (2015a) Multifaceted roles of HSF1 in cancer. Tumour Biol 36:4923–4931. https://doi.org/10.1007/s13277-015-3674-x

    Article  CAS  PubMed  Google Scholar 

  8. Kamal A, Thao L, Sensintaffar J, Zhang L, Boehm MF, Fritz LC et al (2003) A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 425:407–410

    Article  CAS  PubMed  Google Scholar 

  9. Kimura A, Ogata K, Altan B, Yokobori T, Ide M, Mochiki E et al (2016) Nuclear heat shock protein 110 expression is associated with poor prognosis and chemotherapy resistance in gastric cancer. Oncotarget 7:18415–18423. https://doi.org/10.18632/oncotarget.7821

    Article  PubMed  PubMed Central  Google Scholar 

  10. Prodromou C (2016) Mechanisms of Hsp90 regulation. Biochem J 473:2439–2452. https://doi.org/10.1042/BCJ20160005

    Article  CAS  PubMed  Google Scholar 

  11. Rérole AL, Jego G, Garrido C (2011) Hsp70: anti-apoptotic and tumorigenic protein. Methods Mol Biol 787:205–230. https://doi.org/10.1007/978-1-61779-295-3_16

    Article  CAS  PubMed  Google Scholar 

  12. Tang D, Khaleque MA, Jones EL, Theriault JR, Li C, Wong WH et al (2005) Expression of heat shock proteins and heat shock protein messenger ribonucleic acid in human prostate carcinoma in vitro and in tumors in vivo. Cell Stress Chaperones 10:46–58

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Vydra N, Toma A, Glowala-Kosinska M, Gogler-Piglowska A, Widlak W (2013) Overexpression of heat shock transcription factor 1 enhances the resistance of melanoma cells to doxorubicin and paclitaxel. BMC Cancer 13:504. https://doi.org/10.1186/1471-2407-13-504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Jiang L, Kwong DL, Li Y, Liu M, Yuan YF, Li Y et al (2015b) HBP21, a chaperone of heat shock protein 70, functions as a tumor suppressor in hepatocellular carcinoma. Carcinogenesis 36:1111–1120. https://doi.org/10.1093/carcin/bgv116

    Article  CAS  PubMed  Google Scholar 

  15. Zhang TT, Jiang YY, Shang L, Shi ZZ, Liang JW, Wang Z et al (2015) Overexpression of DNAJB6 promotes colorectal cancer cell invasion through an IQGAP1/ERK-dependent signaling pathway. Mol Carcinog 54:1205–1213. https://doi.org/10.1002/mc.22194

    Article  CAS  PubMed  Google Scholar 

  16. Cornford PA, Dodson AR, Parsons KF, Desmond AD, Woolfenden A, Fordham M et al (2000) Heat shock protein expression independently predicts clinical outcome in prostate cancer. Cancer Res 60:7099–7105

    CAS  PubMed  Google Scholar 

  17. Foster CS, Dodson AR, Ambroisine L, Fisher G, Møller H, Clark J et al (2009) Hsp-27 expression at diagnosis predicts poor clinical outcome in prostate cancer independent of ETS-gene rearrangement. Br J Cancer 101:1137–1144. https://doi.org/10.1038/sj.bjc.6605227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Li S, Zhang W, Fan J, Lai Y, Che G (2016) Clinicopathological and prognostic significance of heat shock protein 27 (HSP27) expression in non-small cell lung cancer: a systematic review and meta-analysis. Springerplus 5:1165. https://doi.org/10.1186/s40064-016-2827-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Thomas X, Campos L, Mounier C, Cornillon J, Flandrin P, Le QH et al (2005) Expression of heat-shock proteins is associated with major adverse prognostic factors in acute myeloid leukemia. Leuk Res 29:1049–1058

    Article  CAS  PubMed  Google Scholar 

  20. Yang Z, Zhuang L, Szatmary P, Wen L, Sun H, Lu Y et al (2015a) Upregulation of heat shock proteins (HSPA12A, HSP90B1, HSPA4, HSPA5 and HSPA6) in tumour tissues is associated with poor outcomes from HBV-related early-stage hepatocellular carcinoma. Int J Med Sci 12:256–263. https://doi.org/10.7150/ijms.10735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cheng Q, Chang JT, Geradts J, Neckers LM, Haystead T, Spector NL et al (2012) Amplification and high-level expression of heat shock protein 90 marks aggressive phenotypes of human epidermal growth factor receptor 2 negative breast cancer. Breast Cancer Res 14:R62

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kang GH, Lee EJ, Jang KT, Kim KM, Park CK, Lee CS et al (2010) Expression of HSP90 in gastrointestinal stromal tumours and mesenchymal tumours. Histopathology 56:694–701. https://doi.org/10.1111/j.1365-2559.2010.03550.x

    Article  PubMed  Google Scholar 

  23. Li XS, Xu Q, Fu XY, Luo WS (2014a) Heat shock protein 60 overexpression is associated with the progression and prognosis in gastric cancer. PLoS One 9:e107507. https://doi.org/10.1371/journal.pone.0107507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Collura A, Lagrange A, Svrcek M, Marisa L, Buhard O, Guilloux A et al (2014) Patients with colorectal tumors with microsatellite instability and large deletions in HSP110 T17 have improved response to 5-fluorouracil–based chemotherapy. Gastroenterology 146:401–11.e1

    Article  CAS  PubMed  Google Scholar 

  25. Dai C, Sampson SB (2016) HSF1: guardian of proteostasis in cancer. Trends Cell Biol 26:17–28. https://doi.org/10.1016/j.tcb.2015.10.011

    Article  CAS  PubMed  Google Scholar 

  26. Li S, Ma W, Fei T, Lou Q, Zhang Y, Cui X et al (2014b) Upregulation of heat shock factor 1 transcription activity is associated with hepatocellular carcinoma progression. Mol Med Rep 10:2313–2321. https://doi.org/10.3892/mmr.2014.2547

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Taira T, Negishi Y, Kihara F, Iguchi-Ariga SM, Ariga H (1992) c-myc protein complex binds to two sites in human hsp70 promoter region. Biochim Biophys Acta 1130:166–174

    Article  CAS  PubMed  Google Scholar 

  28. Calderwood SK, Xie Y, Wang X, Khaleque MA, Chou SD, Murshid A et al (2010) Signal transduction pathways leading to heat shock transcription. Sign Transduct Insights 2:13–24

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Home T, Jensen RA, Rao R (2015) Heat shock factor 1 in protein homeostasis and oncogenic signal integration. Cancer Res 75:907–912. https://doi.org/10.1158/0008-5472.CAN-14-2905

    Article  CAS  PubMed  Google Scholar 

  30. Heimberger T, Andrulis M, Riedel S, Stühmer T, Schraud H, Beilhack A et al (2013) The heat shock transcription factor 1 as a potential new therapeutic target in multiple myeloma. Br J Haematol 160:465–476. https://doi.org/10.1111/bjh.12164

    Article  CAS  PubMed  Google Scholar 

  31. Taipale M, Jarosz DF, Lindquist S (2010) HSP90 at the hub of protein homeostasis: emerging mechanistic insights. Nat Rev Mol Cell Biol 11:515–528. https://doi.org/10.1038/nrm2918

    Article  CAS  PubMed  Google Scholar 

  32. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. https://doi.org/10.1016/j.cell.2011.02.013

    Article  CAS  PubMed  Google Scholar 

  33. Miyata Y, Nakamoto H, Neckers L (2013) The therapeutic target Hsp90 and cancer hallmarks. Curr Pharm Des 19:347–365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Neckers L, Workman P (2012) Hsp90 molecular chaperone inhibitors: are we there yet? Clin Cancer Res 18:64–76. https://doi.org/10.1158/1078-0432.CCR-11-1000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Hanahan D, Weinberg RA (2000) Cell 100:57–70

    Article  CAS  PubMed  Google Scholar 

  36. Wang SC, Lien HC, Xia W, Chen IF, Lo HW, Wang Z et al (2004) Binding at and transactivation of the COX-2 promoter by nuclear tyrosine kinase receptor ErbB-2. Cancer Cell 6:251–261

    Article  CAS  PubMed  Google Scholar 

  37. Mohammadi A, Yaghoobi MM, Gholamhoseinian Najar A, Kalantari-Khandani B, Sharifi H, Saravani M (2016) HSP90 inhibition suppresses PGE2 production via modulating COX-2 and 15-PGDH expression in HT-29 colorectal cancer cells. Inflammation 39:1116–1123. https://doi.org/10.1007/s10753-016-0343-1

    Article  CAS  PubMed  Google Scholar 

  38. Tanioka T, Nakatani Y, Kobayashi T, Tsujimoto M, Oh-ishi S, Murakami M et al (2003) Regulation of cytosolic prostaglandin E2 synthase by 90-kDa heat shock protein. Biochem Biophys Res Commun 303:1018–1023

    Article  CAS  PubMed  Google Scholar 

  39. Obermajer N, Wong JL, Edwards RP, Odunsi K, Moysich K, Kalinski P (2012) PGE(2)-driven induction and maintenance of cancer-associated myeloid-derived suppressor cells. Immunol Invest 41:635–657. https://doi.org/10.3109/08820139.2012.695417

    Article  CAS  PubMed  Google Scholar 

  40. Sahin M, Sahin E, Koksoy S (2013) Regulatory T cells in cancer: an overview and perspectives on cyclooxygenase-2 and Foxp3 DNA methylation. Hum Immunol 74:1061–1068. https://doi.org/10.1016/j.humimm.2013.05.009

    Article  CAS  PubMed  Google Scholar 

  41. Agrawal B, Krantz MJ, Reddish MA, Longenecker BM (1998) Cancer-associated MUC1 mucin inhibits human T-cell proliferation, which is reversible by IL-2. Nat Med 4:43–49

    Article  CAS  PubMed  Google Scholar 

  42. Chan AK, Lockhart DC, von Bernstorff W, Spanjaard RA, Joo HG, Eberlein TJ et al (1999) Soluble MUC1 secreted by human epithelial cancer cells mediates immune suppression by blocking T-cell activation. Int J Cancer 82:721–726

    Article  CAS  PubMed  Google Scholar 

  43. Wang J, He P, Gaida M, Yang S, Schetter AJ, Gaedcke J et al (2016) Inducible nitric oxide synthase enhances disease aggressiveness in pancreatic cancer. Oncotarget 7:52993. https://doi.org/10.18632/oncotarget.10323

    Article  PubMed  PubMed Central  Google Scholar 

  44. Yang L, Wang Y, Guo L, Wang L, Chen W, Shi B (2015b) The expression and correlation of iNOS and p53 in oral squamous cell carcinoma. Biomed Res Int 2015:637853. https://doi.org/10.1155/2015/637853

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhang W, He XJ, Ma YY, Wang HJ, Xia YJ, Zhao ZS et al (2011) Inducible nitric oxide synthase expression correlates with angiogenesis, lymphangiogenesis, and poor prognosis in gastric cancer patients. Hum Pathol 42:1275–1282. https://doi.org/10.1016/j.humpath.2010.09.020

    Article  CAS  PubMed  Google Scholar 

  46. Jayaraman P, Parikh F, Lopez-Rivera E, Hailemichael Y, Clark A, Ma G et al (2012) Tumor-expressed inducible nitric oxide synthase controls induction of functional myeloid-derived suppressor cells through modulation of vascular endothelial growth factor release. J Immunol 188:5365–5376. https://doi.org/10.4049/jimmunol.1103553

    Article  CAS  PubMed  Google Scholar 

  47. Singer K, Gottfried E, Kreutz M, Mackensen A (2011) Suppression of T-cell responses by tumor metabolites. Cancer Immunol Immunother 60:425–431. https://doi.org/10.1007/s00262-010-0967-1

    Article  CAS  PubMed  Google Scholar 

  48. Sun X, Sui Q, Zhang C, Tian Z, Zhang J (2013) Targeting blockage of STAT3 in hepatocellular carcinoma cells augments NK cell functions via reverse hepatocellular carcinoma-induced immune suppression. Mol Cancer Ther 12:2885–2896. https://doi.org/10.1158/1535-7163.MCT-12-1087

    Article  CAS  PubMed  Google Scholar 

  49. Zhou YJ, Binder RJ (2014) The heat shock protein-CD91 pathway mediates tumor immune-surveillance. Oncoimmunology 3:e28222

    Article  PubMed  PubMed Central  Google Scholar 

  50. Calderwood SK, Gong J, Murshid A (2016) Extracellular HSPs: the complicated roles of extracellular HSPs in immunity. Front Immunol 7:159. https://doi.org/10.3389/fimmu.2016.00159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Tamura Y, Torigoe T, Kukita K, Saito K, Okuya K, Kutomi G et al (2012) Heat-shock proteins as endogenous ligands building a bridge between innate and adaptive immunity. Immunotherapy 4:841–852. https://doi.org/10.2217/imt.12.75

    Article  CAS  PubMed  Google Scholar 

  52. Basu S, Binder RJ, Ramalingam T, Srivastava PK (2001) CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin. Immunity 14:303–313

    Article  CAS  PubMed  Google Scholar 

  53. Dai J, Liu B, Caudill MM, Zheng H, Qiao Y, Podack ER et al (2003) Cell surface expression of heat shock protein gp96 enhances cross-presentation of cellular antigens and the generation of tumor-specific T cell memory. Cancer Immun 3:1

    PubMed  Google Scholar 

  54. Kepp O, Senovilla L, Vitale I, Vacchelli E, Adjemian S, Agostinis P et al (2014) Consensus guidelines for the detection of immunogenic cell death. Oncoimmunology 3:e955691

    Article  PubMed  PubMed Central  Google Scholar 

  55. Kroemer G, Galluzzi L, Kepp O, Zitvogel L (2013) Immunogenic cell death in cancer therapy. Annu Rev Immunol 31:51–72. https://doi.org/10.1146/annurev-immunol-032712-100008

    Article  CAS  PubMed  Google Scholar 

  56. Zhu H, Fang X, Zhang D, Wu W, Shao M, Wang L et al (2016) Membrane-bound heat shock proteins facilitate the uptake of dying cells and cross-presentation of cellular antigen. Apoptosis 21:96–109. https://doi.org/10.1007/s10495-015-1187-0

    Article  CAS  PubMed  Google Scholar 

  57. Chang CL, Hsu YT, CC W, Yang YC, Wang C, TC W et al (2012) Immune mechanism of the antitumor effects generated by bortezomib. J Immunol 189:3209–3220. https://doi.org/10.4049/jimmunol.1103826

    Article  CAS  PubMed  Google Scholar 

  58. Fucikova J, Kralikova P, Fialova A, Brtnicky T, Rob L, Bartunkova J et al (2011) Human tumor cells killed by anthracyclines induce a tumor-specific immune response. Cancer Res 71:4821–4833. https://doi.org/10.1158/0008-5472.CAN-11-0950

    Article  CAS  PubMed  Google Scholar 

  59. Multhoff G, Pockley AG, Schmid TE, Schilling D (2015) The role of heat shock protein 70 (Hsp70) in radiation-induced immunomodulation. Cancer Lett 368:179–184. https://doi.org/10.1016/j.canlet.2015.02.013

    Article  CAS  PubMed  Google Scholar 

  60. Panzarini E, Inguscio V, Dini L (2013) Immunogenic cell death: can it be exploited in PhotoDynamic Therapy for cancer? Biomed Res Int 2013:482160. https://doi.org/10.1155/2013/482160.

    Article  PubMed  Google Scholar 

  61. Multhoff G, Botzler C, Jennen L, Schmidt J, Ellwart J, Issels R (1997) Heat shock protein 72 on tumor cells: a recognition structure for natural killer cells. J Immunol 158:4341–4350

    CAS  PubMed  Google Scholar 

  62. Chalmin F, Ladoire S, Mignot G, Vincent J, Bruchard M, Remy-Martin JP et al (2010) Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. J Clin Invest 120:457–471. https://doi.org/10.1172/JCI40483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Diao J, Yang X, Song X, Chen S, He Y, Wang Q et al (2015) Exosomal Hsp70 mediates immunosuppressive activity of the myeloid-derived suppressor cells via phosphorylation of Stat3. Med Oncol 32:453. https://doi.org/10.1007/s12032-014-0453-2

    Article  CAS  PubMed  Google Scholar 

  64. Gobbo J, Marcion G, Cordonnier M, Dias AM, Pernet N, Hammann A et al (2015) Restoring anticancer immune response by targeting tumor-derived exosomes with a HSP70 peptide aptamer. J Natl Cancer Inst 108(3). https://doi.org/10.1093/jnci/djv330. pii: djv330

    Article  Google Scholar 

  65. Cho JA, Lee YS, Kim SH, Ko JK, Kim CW (2009) MHC independent anti-tumor immune responses induced by Hsp70-enriched exosomes generate tumor regression in murine models. Cancer Lett 275:256–265. https://doi.org/10.1016/j.canlet.2008.10.021

    Article  CAS  PubMed  Google Scholar 

  66. Binder RJ, Zhou YJ, Messmer MN, Pawaria S (2012) CD91-dependent modulation of immune responses by heat shock proteins: a role in autoimmunity. Autoimmune Dis 2012:863041. https://doi.org/10.1155/2012/863041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Chandawarkar RY, Wagh MS, Kovalchin JT, Srivastava P (2004) Immune modulation with high-dose heat-shock protein gp96: therapy of murine autoimmune diabetes and encephalomyelitis. Int Immunol 16:615–624

    Article  CAS  PubMed  Google Scholar 

  68. Chandawarkar RY, Wagh MS, Srivastava PK (1999) The dual nature of specific immunological activity of tumor-derived gp96 preparations. J Exp Med 189:1437–1442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Akyol S, Gercel-Taylor C, Reynolds LC, Taylor DD (2006) HSP-10 in ovarian cancer: expression and suppression of T-cell signaling. Gynecol Oncol 101:481–486

    Article  CAS  PubMed  Google Scholar 

  70. Banerjee S, Lin CF, Skinner KA, Schiffhauer LM, Peacock J, Hicks DG et al (2011) Heat shock protein 27 differentiates tolerogenic macrophages that may support human breast cancer progression. Cancer Res 71:318–327. https://doi.org/10.1158/0008-5472.CAN-10-1778

    Article  CAS  PubMed  Google Scholar 

  71. van Roon JA, van Eden W, van Roy JL, Lafeber FJ, Bijlsma JW (1997) Stimulation of suppressive T cell responses by human but not bacterial 60-kD heat-shock protein in synovial fluid of patients with rheumatoid arthritis. J Clin Invest 100:459–463

    Article  PubMed  PubMed Central  Google Scholar 

  72. Zonneveld-Huijssoon E, Roord ST, de Jager W, Klein M, Albani S, Anderton SM et al (2011) Bystander suppression of experimental arthritis by nasal administration of a heat shock protein peptide. Ann Rheum Dis 70:2199–2206. https://doi.org/10.1136/ard.2010.136994

    Article  CAS  PubMed  Google Scholar 

  73. Kilmartin B, Reen DJ (2004) HSP60 induces self-tolerance to repeated HSP60 stimulation and cross-tolerance to other pro-inflammatory stimuli. Eur J Immunol 34:2041–2051

    Article  CAS  PubMed  Google Scholar 

  74. Zhong Y, Tang H, Wang X, Zeng Q, Liu Y, Zhao XI et al (2016) Intranasal immunization with heat shock protein 60 induces CD4+ CD25+ GARP+ and type 1 regulatory T cells and inhibits early atherosclerosis. Clin Exp Immunol 183:452–468. https://doi.org/10.1111/cei.12726

    Article  CAS  PubMed  Google Scholar 

  75. Wachstein J, Tischer S, Figueiredo C, Limbourg A, Falk C, Immenschuh S et al (2012) HSP70 enhances immunosuppressive function of CD4+CD25+FoxP3+ T regulatory cells and cytotoxicity in CD4+CD25neg T cells. PLoS One 7:e51747. https://doi.org/10.1371/journal.pone.0051747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Li X, Liu Z, Yan X, Zhang X, Li Y, Zhao B et al (2013) Induction of regulatory T cells by high-dose gp96 suppresses murine liver immune hyperactivation. PLoS One 8:e68997. https://doi.org/10.1371/journal.pone.0068997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. De Filippo A, Binder RJ, Camisaschi C, Beretta V, Arienti F, Villa A et al (2008) Human plasmacytoid dendritic cells interact with gp96 via CD91 and regulate inflammatory responses. J Immunol 181:6525–6535

    Article  PubMed  Google Scholar 

  78. Kinner L, Sedlacek AL, Watkins SC, Binder RJ (2016) Gp96 initiates DNA methylome remodeling in dendritic cells and facilitates interaction with T cells. J Immunol 196:S59.25

    Google Scholar 

  79. Herber DL, Cao W, Nefedova Y, Novitskiy SV, Nagaraj S, Tyurin VA et al (2010) Lipid accumulation and dendritic cell dysfunction in cancer. Nat Med 16:880–886. https://doi.org/10.1038/nm.2172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Qian J, Yi H, Guo C, Yu X, Zuo D, Chen X et al (2011) CD204 suppresses large heat shock protein-facilitated priming of tumor antigen gp100-specific T cells and chaperone vaccine activity against mouse melanoma. J Immunol 187:2905–2914. https://doi.org/10.4049/jimmunol.1100703

    Article  CAS  PubMed  Google Scholar 

  81. Shevtsov M, Multhoff G (2016) Heat shock protein-peptide and HSP-based immunotherapies for the treatment of cancer. Front Immunol 7:171. https://doi.org/10.3389/fimmu.2016.00171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Li JL, Liu HL, Zhang XR, JP X, WK H, Liang M et al (2009) A phase I trial of intratumoral administration of recombinant oncolytic adenovirus overexpressing HSP70 in advanced solid tumor patients. Gene Ther 16:376–382. https://doi.org/10.1038/gt.2008.179

    Article  CAS  PubMed  Google Scholar 

  83. Maeda Y, Yoshimura K, Matsui H, Shindo Y, Tamesa T, Tokumitsu Y et al (2015) Dendritic cells transfected with heat-shock protein 70 messenger RNA for patients with hepatitis C virus-related hepatocellular carcinoma: a phase 1 dose escalation clinical trial. Cancer Immunol Immunother 64:1047–1056. https://doi.org/10.1007/s00262-015-1709-1

    Article  CAS  PubMed  Google Scholar 

  84. Shevtsov MA, Kim AV, Samochernych KA, Romanova IV, Margulis BA, Guzhova IV et al (2014) Pilot study of intratumoral injection of recombinant heat shock protein 70 in the treatment of malignant brain tumors in children. Onco Targets Ther 7:1071–1081. https://doi.org/10.2147/OTT.S62764

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. He S, Smith DL, Sequeira M, Sang J, Bates RC, Proia DA (2014) The HSP90 inhibitor ganetespib has chemosensitizer and radiosensitizer activity in colorectal cancer. Invest New Drugs 32:577–586. https://doi.org/10.1007/s10637-014-0095-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Isaacs JS (2016) Hsp90 as a “Chaperone” of the epigenome: insights and opportunities for cancer therapy. Adv Cancer Res 129:107–140. https://doi.org/10.1016/bs.acr.2015.09.003

    Article  PubMed  Google Scholar 

  87. Neckers L, Ivy SP (2003) Heat shock protein 90. Curr Opin Oncol 15:419–424

    Article  CAS  PubMed  Google Scholar 

  88. Proia DA, Kaufmann GF (2015) Targeting heat-shock protein 90 (HSP90) as a complementary strategy to immune checkpoint blockade for cancer therapy. Cancer Immunol Res 3:583–589. https://doi.org/10.1158/2326-6066.CIR-15-0057

    Article  CAS  PubMed  Google Scholar 

  89. Trepel J, Mollapour M, Giaccone G, Neckers L (2010) Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer 10:537–549. https://doi.org/10.1038/nrc2887

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Wang Y, Trepel JB, Neckers LM, Giaccone G (2010) STA-9090, a small-molecule Hsp90 inhibitor for the potential treatment of cancer. Curr Opin Investig Drugs 11:1466–1476

    CAS  PubMed  Google Scholar 

  91. Graner MW (2016) HSP90 and immune modulation in cancer. Adv Cancer Res 129:191–224. https://doi.org/10.1016/bs.acr.2015.10.001

    Article  PubMed  Google Scholar 

  92. Rao A, Taylor JL, Chi-Sabins N, Kawabe M, Gooding WE, Storkus WJ (2012a) Combination therapy with HSP90 inhibitor 17-DMAG reconditions the tumor microenvironment to improve recruitment of therapeutic T cells. Cancer Res 72:3196–3206. https://doi.org/10.1158/0008-5472.CAN-12-0538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Rao A, Lowe DB, Storkus WJ (2012b) Shock block for improved immunotherapy. Oncoimmunology 1:1427–1429

    Article  PubMed  PubMed Central  Google Scholar 

  94. Rao R, Fiskus W, Ganguly S, Kambhampati S, Bhalla KN (2012c) HDAC inhibitors and chaperone function. Adv Cancer Res 116:239–262. https://doi.org/10.1016/B978-0-12-394387-3.00007-0

    Article  CAS  PubMed  Google Scholar 

  95. Garcia-Lora A, Algarra I, Garrido F (2003) MHC class I antigens, immune surveillance, and tumor immune escape. J Cell Physiol 195:346–355

    Article  CAS  PubMed  Google Scholar 

  96. Kessler BM, Glas R, Ploegh HL (2002) MHC class I antigen processing regulated by cytosolic proteolysis-short cuts that alter peptide generation. Mol Immunol 39:171–179

    Article  CAS  PubMed  Google Scholar 

  97. Storkus WJ, Herrem C, Kawabe M, Cohen PA, Bukowski RM, Finke JH et al (2007) Improving immunotherapy by conditionally enhancing MHC class I presentation of tumor antigen-derived Peptide epitopes. Crit Rev Immunol 27:485–493

    Article  CAS  PubMed  Google Scholar 

  98. Wang RF (2001) The role of MHC class II-restricted tumor antigens and CD4+ T cells in antitumor immunity. Trends Immunol 22:269–276

    Article  PubMed  Google Scholar 

  99. Makkouk A, Weiner GJ (2015) Cancer immunotherapy and breaking immune tolerance: new approaches to an old challenge. Cancer Res 75:5–10. https://doi.org/10.1158/0008-5472.CAN-14-2538

    Article  CAS  PubMed  Google Scholar 

  100. Haggerty TJ, Dunn IS, Rose LB, Newton EE, Pandolfi F, Kurnick JT (2014) Heat shock protein-90 inhibitors enhance antigen expression on melanomas and increase T cell recognition of tumor cells. PLoS One 9:e114506. https://doi.org/10.1371/journal.pone.0114506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Kawabe M, Mandic M, Taylor JL, Vasquez CA, Wesa AK, Neckers LM et al (2009) Heat shock protein 90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin enhances EphA2+ tumor cell recognition by specific CD8+ T cells. Cancer Res 69:6995–7003. https://doi.org/10.1158/0008-5472.CAN-08-4511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Lin CC, Tu CF, Yen MC, Chen MC, Hsieh WJ, Chang WC et al (2007) Inhibitor of heat-shock protein 90 enhances the antitumor effect of DNA vaccine targeting clients of heat-shock protein. Mol Ther 15:404–410

    Article  CAS  PubMed  Google Scholar 

  103. Lampen MH, van Hall T (2011) Strategies to counteract MHC-I defects in tumors. Curr Opin Immunol 23:293–298. https://doi.org/10.1016/j.coi.2010.12.005

    Article  CAS  PubMed  Google Scholar 

  104. Leone P, Shin EC, Perosa F, Vacca A, Dammacco F, Racanelli V (2013) MHC class I antigen processing and presenting machinery: organization, function, and defects in tumor cells. J Natl Cancer Inst 105:1172–1187. https://doi.org/10.1093/jnci/djt184

    Article  CAS  PubMed  Google Scholar 

  105. Seliger B (2014) The link between MHC class I abnormalities of tumors, oncogenes, tumor suppressor genes, and transcription factors. J Immunotoxicol 11:308–310. https://doi.org/10.3109/1547691X.2013.875084

    Article  CAS  PubMed  Google Scholar 

  106. Castilleja A, Ward NE, O’Brian CA, Swearingen B II, Swan E, Gillogly MA et al (2001) Accelerated HER-2 degradation enhances ovarian tumor recognition by CTL. Implications for tumor immunogenicity. Mol Cell Biochem 217:21–33

    Article  CAS  PubMed  Google Scholar 

  107. Businaro R, Profumo E, Tagliani A, Buttari B, Leone S, D’Amati G et al (2009) Heat-shock protein 90: a novel autoantigen in human carotid atherosclerosis. Atherosclerosis 207:74–83. https://doi.org/10.1016/j.atherosclerosis.2009.04.026

    Article  CAS  PubMed  Google Scholar 

  108. Direskeneli H, Ekşioglu-Demiralp E, Yavuz S, Ergun T, Shinnick T, Lehner T et al (2000) T cell responses to 60/65 kDa heat shock protein derived peptides in Turkish patients with Behçet’s disease. J Rheumatol 27:708–713

    CAS  PubMed  Google Scholar 

  109. Li R, Qian J, Zhang W, Fu W, Du J, Jiang H et al (2014c) Human heat shock protein-specific cytotoxic T lymphocytes display potent anti-tumour immunity in multiple myeloma. Br J Haematol 166:690–701. https://doi.org/10.1111/bjh.12943

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Miconnet I, Salcedo M, Chouaib S, Lemonnier FA, Abastado JP, Kosmatopoulos K (2007) Induction of multiple CD8+ T cell responses against the inducible Hsp70 employing an Hsp70 oligoepitope peptide. Oncol Rep 17:679–685

    PubMed  Google Scholar 

  111. Van Herwijnen MJ, Van Der Zee R, Van Eden W, Broere F (2013) Heat shock proteins can be targets of regulatory T cells for therapeutic intervention in rheumatoid arthritis. Int J Hyperthermia 29:448–454. https://doi.org/10.3109/02656736.2013.811546

    Article  CAS  PubMed  Google Scholar 

  112. Song D, Chaerkady R, Tan AC, García-García E, Nalli A, Suárez-Gauthier A et al (2008) Antitumor activity and molecular effects of the novel heat shock protein 90 inhibitor, IPI-504, in pancreatic cancer. Mol Cancer Ther 7:3275–3284. https://doi.org/10.1158/1535-7163.MCT-08-0508

    Article  CAS  PubMed  Google Scholar 

  113. Yamano T, Mizukami S, Murata S, Chiba T, Tanaka K, Udono H (2008) Hsp90-mediated assembly of the 26 S proteasome is involved in major histocompatibility complex class I antigen processing. J Biol Chem 283:28060–28065. https://doi.org/10.1074/jbc.M803077200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Rajagopal D, Bal V, Mayor S, George A, Rath S (2006) A role for the Hsp90 molecular chaperone family in antigen presentation to T lymphocytes via major histocompatibility complex class II molecules. Eur J Immunol 36:828–841

    Article  CAS  PubMed  Google Scholar 

  115. Zhou D, Blum JS (2004) Presentation of cytosolic antigens via MHC class II molecules. Immunol Res 30:279–290

    Article  CAS  PubMed  Google Scholar 

  116. Maj T, Wei S, Welling T, Zou W (2013) T cells and costimulation in cancer. Cancer J 19:473–482. https://doi.org/10.1097/PPO.0000000000000002

    Article  CAS  PubMed  Google Scholar 

  117. Baumeister SH, Freeman GJ, Dranoff G, Sharpe AH (2016) Coinhibitory pathways in immunotherapy for cancer. Annu Rev Immunol 34:539–573. https://doi.org/10.1146/annurev-immunol-032414-112049

    Article  CAS  PubMed  Google Scholar 

  118. Berges C, Bedke T, Stuehler C, Khanna N, Zehnter S et al (2015) Combined PI3K/Akt and Hsp90 targeting synergistically suppresses essential functions of alloreactive T cells and increases Tregs. J Leukoc Biol 98:1091–1105. https://doi.org/10.1189/jlb.5A0814-413R

    Article  CAS  PubMed  Google Scholar 

  119. Collins CB, Aherne CM, Yeckes A, Pound K, Eltzschig HK, Jedlicka P et al (2013) Inhibition of N-terminal ATPase on HSP90 attenuates colitis through enhanced Treg function. Mucosal Immunol 6:960–971. https://doi.org/10.1038/mi.2012.134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Collins CB, Strassheim D, Aherne CM, Yeckes AR, Jedlicka P, de Zoeten EF (2014) Targeted inhibition of heat shock protein 90 suppresses tumor necrosis factor-α and ameliorates murine intestinal inflammation. Inflamm Bowel Dis 20:685–694. https://doi.org/10.1097/01.MIB.0000442839.28664.75

    Article  PubMed  Google Scholar 

  121. de Zoeten EF, Wang L, Butler K, Beier UH, Akimova T, Sai H et al (2011) Histone deacetylase 6 and heat shock protein 90 control the functions of Foxp3(+) T-regulatory cells. Mol Cell Biol 31:2066–2078. https://doi.org/10.1128/MCB.05155-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Stenderup K, Rosada C, Gavillet B, Vuagniaux G, Dam TN (2014) Debio 0932, a new oral Hsp90 inhibitor, alleviates psoriasis in a xenograft transplantation model. Acta Derm Venereol 94(6):672. https://doi.org/10.2340/00015555-1838

    Article  CAS  PubMed  Google Scholar 

  123. Bae J, Munshi A, Li C, Samur M, Prabhala R, Mitsiades C et al (2013) Heat shock protein 90 is critical for regulation of phenotype and functional activity of human T lymphocytes and NK cells. J Immunol 190:1360–1371. https://doi.org/10.4049/jimmunol.1200593

    Article  CAS  PubMed  Google Scholar 

  124. Huyan T, Li Q, Dong DD, Yang H, Zhang J, Huang QS et al (2016) Heat shock protein 90 inhibitors induce functional inhibition of human natural killer cells in a dose-dependent manner. Immunopharmacol Immunotoxicol 38:77–86. https://doi.org/10.3109/08923973.2015.1119159

    Article  CAS  PubMed  Google Scholar 

  125. Trojandt S, Reske-Kunz AB, Bros M (2014) Geldanamycin-mediated inhibition of heat shock protein 90 partially activates dendritic cells, but interferes with their full maturation, accompanied by impaired upregulation of RelB. J Exp Clin Cancer Res 33:16. https://doi.org/10.1186/1756-9966-33-16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Tukaj S, Tiburzy B, Manz R, de Castro Marques A, Orosz A, Ludwig RJ et al (2014a) Immunomodulatory effects of heat shock protein 90 inhibition on humoral immune responses. Exp Dermatol 23:585–590. https://doi.org/10.1111/exd.12476

    Article  CAS  PubMed  Google Scholar 

  127. Tukaj S, Zillikens D, Kasperkiewicz M (2014b) Inhibitory effects of heat shock protein 90 blockade on proinflammatory human Th1 and Th17 cell subpopulations. J Inflamm (Lond) 11:10. https://doi.org/10.1186/1476-9255-11-10

    Article  CAS  Google Scholar 

  128. Giannini A, Bijlmakers MJ (2004) Regulation of the Src family kinase Lck by Hsp90 and ubiquitination. Mol Cell Biol 24:5667–5676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Grune T, Jung T, Merker K, Davies KJ (2004) Decreased proteolysis caused by protein aggregates, inclusion bodies, plaques, lipofuscin, ceroid, and ‘aggresomes’ during oxidative stress, aging, and disease. Int J Biochem Cell Biol 36:2519–2530

    Article  CAS  PubMed  Google Scholar 

  130. Hayashi K, Kamikawa Y (2011) HSP90 is crucial for regulation of LAT expression in activated T cells. Mol Immunol 48:941–946. https://doi.org/10.1016/j.molimm.2010.12.014

    Article  CAS  PubMed  Google Scholar 

  131. Tsuji T, Matsuzaki J, Caballero OL, Jungbluth AA, Ritter G, Odunsi K et al (2012) Heat shock protein 90-mediated peptide-selective presentation of cytosolic tumor antigen for direct recognition of tumors by CD4+ T cells. J Immunol 188(8):3851. https://doi.org/10.4049/jimmunol.1103269

    Article  CAS  PubMed  Google Scholar 

  132. Salimu J, Spary LK, Al-Taei S, Clayton A, Mason MD, Staffurth J et al (2015) Cross-presentation of the oncofetal tumor antigen 5T4 from irradiated prostate cancer cells--a key role for heat-shock protein 70 and receptor CD91. Cancer Immunol Res 3:678–688. https://doi.org/10.1158/2326-6066.CIR-14-0079

    Article  CAS  PubMed  Google Scholar 

  133. Bae J, Mitsiades C, Tai YT, Bertheau R, Shammas M, Batchu RB, Li C, Catley L, Prabhala R, Anderson KC, Munshi NC (2007) Phenotypic and functional effects of heat shock protein 90 inhibition on dendritic cells. J Immunol 178:7730–7737. PMID: 17548610

    Article  CAS  PubMed  Google Scholar 

  134. Bao R, Lai CJ, Qu H, Wang D, Yin L, Zifcak B et al (2009) CUDC-305, a novel synthetic HSP90 inhibitor with unique pharmacologic properties for cancer therapy. Clin Cancer Res 15:4046–4057. https://doi.org/10.1158/1078-0432.CCR-09-0152

    Article  CAS  PubMed  Google Scholar 

  135. Graham B, Curry J, Smyth T, Fazal L, Feltell R, Harada I et al (2012) The heat shock protein 90 inhibitor, AT13387, displays a long duration of action in vitro and in vivo in non-small cell lung cancer. Cancer Sci 103:522–527. https://doi.org/10.1111/j.1349-7006.2011.02191.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Holland JP, Caldas-Lopes E, Divilov V, Longo VA, Taldone T, Zatorska D et al (2010) Measuring the pharmacodynamic effects of a novel Hsp90 inhibitor on HER2/neu expression in mice using Zr-DFO-trastuzumab. PLoS One 5:e8859. https://doi.org/10.1371/journal.pone.0008859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Sydor JR, Normant E, Pien CS, Porter JR, Ge J, Grenier L et al (2006) Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90. Proc Natl Acad Sci U S A 103:17408–17413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Fogliatto G, Gianellini L, Brasca MG, Casale E, Ballinari D, Ciomei M et al (2013) NMS-E973, a novel synthetic inhibitor of Hsp90 with activity against multiple models of drug resistant target agents, including intracranial metastases. Clin Cancer Res 19:3520–3532. https://doi.org/10.1158/1078-0432.CCR-12-3512

    Article  CAS  PubMed  Google Scholar 

  139. Liu C, Workman CJ, Vignali DA (2016) Targeting regulatory T cells in tumors. FEBS J 283:2731–2748. https://doi.org/10.1111/febs.13656

    Article  CAS  PubMed  Google Scholar 

  140. Mendler AN, Hu B, Prinz PU, Kreutz M, Gottfried E, Noessner E (2012) Tumor lactic acidosis suppresses CTL function by inhibition of p38 and JNK/c-Jun activation. Int J Cancer 131:633–640. https://doi.org/10.1002/ijc.26410

    Article  CAS  PubMed  Google Scholar 

  141. Pyzer AR, Cole L, Rosenblatt J, Avigan DE (2016) Myeloid-derived suppressor cells as effectors of immune suppression in cancer. Int J Cancer 139:1915–1926. https://doi.org/10.1002/ijc.30232

    Article  CAS  PubMed  Google Scholar 

  142. Sitkovsky MV, Kjaergaard J, Lukashev D, Ohta A (2008) Hypoxia-adenosinergic immunosuppression: tumor protection by T regulatory cells and cancerous tissue hypoxia. Clin Cancer Res 14:5947–5952. https://doi.org/10.1158/1078-0432.CCR-08-0229

    Article  CAS  PubMed  Google Scholar 

  143. Conejo-Garcia JR, Benencia F, Courreges MC, Kang E, Mohamed-Hadley A, Buckanovich RJ et al (2004) Tumor-infiltrating dendritic cell precursors recruited by a β-defensin contribute to vasculogenesis under the influence of VEGF-A. Nat Med 10:950–958

    Article  CAS  PubMed  Google Scholar 

  144. Goel S, Wong AH, Jain RK (2012) Vascular normalization as a therapeutic strategy for malignant and nonmalignant disease. Cold Spring Harb Perspect Med 2:a006486. https://doi.org/10.1101/cshperspect.a006486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Gottfried E, Kreutz M, Haffner S, Holler E, Iacobelli M, Andreesen R et al (2007) Differentiation of human tumour-associated dendritic cells into endothelial-like cells: an alternative pathway of tumour angiogenesis. Scand J Immunol 65:329–335

    Article  CAS  PubMed  Google Scholar 

  146. Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62

    Article  CAS  PubMed  Google Scholar 

  147. Stockmann C, Schadendorf D, Klose R, Helfrich I (2014) The impact of the immune system on tumor: angiogenesis and vascular remodeling. Front Oncol 4:69. https://doi.org/10.3389/fonc.2014.00069

    Article  PubMed  PubMed Central  Google Scholar 

  148. Yang L, DeBusk LM, Fukuda K, Fingleton B, Green-Jarvis B, Shyr Y et al (2004) Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 6:409–421

    Article  CAS  PubMed  Google Scholar 

  149. Huang Y, Goel S, Duda DG, Fukumura D, Jain RK (2013) Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Res 73:2943–2948. https://doi.org/10.1158/0008-5472.CAN-12-4354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Topalian SL, Drake CG, Pardoll DM (2015) Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27:450–461. https://doi.org/10.1016/j.ccell.2015.03.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Bali P, Pranpat M, Bradner J, Balasis M, Fiskus W, Guo F et al (2005) Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. J Biol Chem 280:26729–26734

    Article  CAS  PubMed  Google Scholar 

  152. Ganai SA (2016) Histone deacetylase inhibitors modulating non-epigenetic players: the novel molecular targets for therapeutic intervention. Curr Drug Targets. PubMed PMID: 27231104

    Google Scholar 

  153. Seidel C, Schnekenburger M, Mazumder A, Teiten MH, Kirsch G, Dicato M et al (2016) 4-Hydroxybenzoic acid derivatives as HDAC6-specific inhibitors modulating microtubular structure and HSP90α chaperone activity against prostate cancer. Biochem Pharmacol 99:31–52. https://doi.org/10.1016/j.bcp.2015.11.005

    Article  CAS  PubMed  Google Scholar 

  154. Kroesen M, Gielen P, Brok IC, Armandari I, Hoogerbrugge PM, Adema GJ (2014) HDAC inhibitors and immunotherapy; a double edged sword? Oncotarget 5:6558–6572

    Article  PubMed  PubMed Central  Google Scholar 

  155. Schotterl S, Brennenstuhl H, Naumann U (2015) Modulation of immune responses by histone deacetylase inhibitors. Crit Rev Oncog 20:139–154

    Article  PubMed  Google Scholar 

  156. Shen L, Orillion A, Pili R (2016) Histone deacetylase inhibitors as immunomodulators in cancer therapeutics. Epigenomics 8:415–428. https://doi.org/10.2217/epi.15.118

    Article  CAS  PubMed  Google Scholar 

  157. Gameiro SR, Malamas AS, Tsang KY, Ferrone S, Hodge JW (2016) Inhibitors of histone deacetylase 1 reverse the immune evasion phenotype to enhance T-cell mediated lysis of prostate and breast carcinoma cells. Oncotarget 7:7390–7402. https://doi.org/10.18632/oncotarget.7180

    Article  PubMed  PubMed Central  Google Scholar 

  158. Lisiero DN, Soto H, Everson RG, Liau LM, Prins RM (2014) The histone deacetylase inhibitor, LBH589, promotes the systemic cytokine and effector responses of adoptively transferred CD8+ T cells. J Immunother Cancer 2:8. https://doi.org/10.1186/2051-1426-2-8

    Article  PubMed  PubMed Central  Google Scholar 

  159. Tiper IV, Webb TJ (2016) Histone deacetylase inhibitors enhance CD1d-dependent NKT cell responses to lymphoma. Cancer Immunol Immunother 65:1411. PubMed PMID: 27614429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Cao K, Wang G, Li W, Zhang L, Wang R, Huang Y et al (2015) Histone deacetylase inhibitors prevent activation-induced cell death and promote anti-tumor immunity. Oncogene 34:5960–5970. https://doi.org/10.1038/onc.2015.46

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Lee SY, Huang Z, Kang TH, Soong RS, Knoff J, Axenfeld E et al (2013) Histone deacetylase inhibitor AR-42 enhances E7-specific CD8+ T cell-mediated antitumor immunity induced by therapeutic HPV DNA vaccination. J Mol Med (Berl) 91:1221–1231

    Article  CAS  Google Scholar 

  162. Song DG, Ye Q, Santoro S, Fang C, Best A, Powell DJ Jr (2013) Chimeric NKG2D CAR-expressing T cell-mediated attack of human ovarian cancer is enhanced by histone deacetylase inhibition. Hum Gene Ther 24:295–305. https://doi.org/10.1089/hum.2012.143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Woods DM, Sodré AL, Villagra A, Sarnaik A, Sotomayor EM, Weber J (2015) HDAC inhibition upregulates PD-1 ligands in melanoma and augments immunotherapy with PD-1 blockade. Cancer Immunol Res 3:1375–1385. https://doi.org/10.1158/2326-6066.CIR-15-0077-T

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by NIH R01 CA169118 (WJS) and NIH P50 CA121973 CA (Career Enhancement Award to RJF).

Author information

Authors and Affiliations

  1. Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Ronald J. Fecek & Walter J. Storkus

  2. Department of Human Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Subhara Raveendran

  3. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Manoj Chelvanambi & Walter J. Storkus

  4. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Walter J. Storkus

  5. Department of Bioengineering, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Walter J. Storkus

  6. University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA

    Walter J. Storkus

  7. Melanoma Program of the University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    Walter J. Storkus

Authors
  1. Ronald J. Fecek
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Subhara Raveendran
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Manoj Chelvanambi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Walter J. Storkus
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Walter J. Storkus .

Editor information

Editors and Affiliations

  1. Department of Immunology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, USA

    Robert J. Binder

  2. Carole and Ray Neag Comprehensive Cancer Center and the Department of Immunology, University of Connecticut School of Medicine, Farmington, Connecticut, USA

    Pramod K. Srivastava

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Fecek, R.J., Raveendran, S., Chelvanambi, M., Storkus, W.J. (2018). Inhibition of HSPs for Enhanced Immunity. In: Binder, R., Srivastava, P. (eds) Heat Shock Proteins in the Immune System. Springer, Cham. https://doi.org/10.1007/978-3-319-69042-1_9

Download citation

Publish with us

Policies and ethics

Search

Navigation