Abstract:
Heat Shock Proteins (HSP) are a diverse group of proteins that as molecular chaperons bind to a variety of cell proteins in all cells. HSP also play a significant role in helping the immune system recognize diseased cells. During the past three decades, HSP are found to be a potent agent for tumor immunotherapy and studies towards anti-tumor vaccine development still continue today. HSP-based immunotherapies, which could augment antigen-specific immune responses, are the promising approaches for effective treatment and enduring cure. However, more studies on the role of HSP to induce innate and adaptive immune responses have resulted in new understanding of HSP in immunotherapy. Certain HSP are over expressed in tumor cells and aid tumor cells metastasis. Under this circumstance, HSP were chosen as targets for cancer treatments. Recent evidence further demonstrated that HSP possess immunoregulatory attributes. The high evolutionary conservancy of HSP and their overexpression during inflammation make them as important pathogen-related antigens as well as self antigens. Certain HSP (specifically Hsp60, Hsp65, Hsp70 and Hsp10) have been identified to be involved in the regulation of some autoimmune diseases. Now HSP becomes a double-sided sword. Therefore, HSP are also a tool for manipulating autoimmune inflammation and HSP for immunotherapy of autoimmune diseases are under discovery
Keywords:
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsAbbreviations
- AIA:
-
adjuvant induced arthritis
- APC:
-
antigen presenting cells
- BCG:
-
Bacillus Calmette-Guérin
- CTL:
-
cytotoxic T lymphocytes
- DC:
-
dendritic cells
- ERK:
-
extracellular-signal regulated kinase
- Grp:
-
glucose regulated proteins
- HER:
-
human endothelial growth factor receptor
- HLA:
-
human leukocyte antigen system
- HPV:
-
human papilloma virus
- HSF:
-
heat shock factor
- Hsp:
-
heat shock proteins
- hsp :
-
heat shock protein gene
- HSP:
-
heat shock protein family
- HSP :
-
heat shock protein family gene
- ICD:
-
intracellular domain
- IDDM:
-
insulin-dependent diabetes mellitus
- IFA:
-
incomplete Freund’s adjuvant
- IL:
-
interleukin
- NHL:
-
non-Hodgkin lymphoma
- NO:
-
nitric oxide
- NOD:
-
non-obese diabetic
- RA:
-
rheumatoid arthritis
- RCC:
-
renal cell carcinoma
- RRP:
-
recurrent respiratory papillomatosis
- TAA:
-
tumor-associated antigens
- TGF-β:
-
transforming growth factor-beta
- TNF-α:
-
tumor necrosis factor-alpha
References
Aalamian, M., Fuchs, E., Gupta, R. and Levey, D. L. (2006) Autologous renal cell cancer vaccines using heat shock protein-peptide complexes. Urol Oncol 24, 425–33.
Aloy, M. T., Hadchity, E., Bionda, C., Diaz-Latoud, C., Claude, L., Rousson, R., Arrigo, A. P. and Rodriguez-Lafrasse, C. (2008) Protective role of Hsp27 protein against gamma radiation-induced apoptosis and radiosensitization effects of Hsp27 gene silencing in different human tumor cells. Int J Radiat Oncol Biol Phys 70, 543–53.
Antigenics, I. (2006) Antigenics Announces Results From In-Depth Analysis of Phase 3 Data of Oncophage in Kidney Cancer and Provides Regulatory Update. Press Release.
Antigenics, I. (2008) Oncophage Approved in Russia for the Treatment of Internediate-Risk Kidney Cancer.
Asea, A. (2005) Stress proteins and initiation of immune response: chaperokine activity of hsp72. Exerc Immunol Rev 11, 34–45.
Asea, A., Kraeft, S. K., Kurt-Jones, E. A., Stevenson, M. A., Chen, L. B., Finberg, R. W., Koo, G. C. and Calderwood, S. K. (2000) HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med 6, 435–42.
Banerji, U., O’Donnell, A., Scurr, M., Pacey, S., Stapleton, S., Asad, Y., Simmons, L., Maloney, A., Raynaud, F., Campbell, M., Walton, M., Lakhani, S., Kaye, S., Workman, P. and Judson, I. (2005) Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies. J Clin Oncol 23, 4152–61.
Basu, S. and Srivastava, P. K. (1999) Calreticulin, a peptide-binding chaperone of the endoplasmic reticulum, elicits tumor- and peptide-specific immunity. J Exp Med 189, 797–802.
Bausero, M. A., Bharti, A., Page, D. T., Perez, K. D., Eng, J. W., Ordonez, S. L., Asea, E. E., Jantschitsch, C., Kindas-Muegge, I., Ciocca, D. and Asea, A. (2005) Silencing the hsp25 gene eliminates migration capability of the highly metastatic murine 4T1 breast adenocarcinoma cell. Tumour Biol 27, 17–26.
Bausero, M. A., Page, D. T., Osinaga, E. and Asea, A. (2004) Surface expression of Hsp25 and Hsp72 differentially regulates tumor growth and metastasis. Tumour Biol 25, 243–51.
Belli, F., Testori, A., Rivoltini, L., Maio, M., Andreola, G., Sertoli, M. R., Gallino, G., Piris, A., Cattelan, A., Lazzari, I., Carrabba, M., Scita, G., Santantonio, C., Pilla, L., Tragni, G., Lombardo, C., Arienti, F., Marchiano, A., Queirolo, P., Bertolini, F., Cova, A., Lamaj, E., Ascani, L., Camerini, R., Corsi, M., Cascinelli, N., Lewis, J. J., Srivastava, P. and Parmiani, G. (2002) Vaccination of metastatic melanoma patients with autologous tumor-derived heat shock protein gp96-peptide complexes: clinical and immunologic findings. J Clin Oncol 20, 4169–80.
Benagiano, M., D’Elios, M. M., Amedei, A., Azzurri, A., van der Zee, R., Ciervo, A., Rombola, G., Romagnani, S., Cassone, A. and Del Prete, G. (2005) Human 60-kDa heat shock protein is a target autoantigen of T cells derived from atherosclerotic plaques. J Immunol 174, 6509–17.
Blasi, C. (2008) The autoimmune origin of atherosclerosis. Atherosclerosis 201, 17–32.
Calderwood, S. K., Theriault, J. R. and Gong, J. (2005) Message in a bottle: role of the 70-kDa heat shock protein family in anti-tumor immunity. Eur J Immunol 35, 2518–27.
Campisi, J. and Fleshner, M. (2003) Role of extracellular HSP72 in acute stress-induced potentiation of innate immunity in active rats. J Appl Physiol 94, 43–52.
Chen, C. H., Wang, T. L., Hung, C. F., Yang, Y., Young, R. A., Pardoll, D. M. and Wu, T. C. (2000) Enhancement of DNA vaccine potency by linkage of antigen gene to an HSP70 gene. Cancer Res 60, 1035–42.
Chu, N. R., Wu, H. B., Wu, T. C., Boux, L. J., Mizzen, L. A. and Siegel, M. I. (2000a) Immunotherapy of a human papillomavirus type 16 E7-expressing tumor by administration of fusion protein comprised of Mycobacterium bovis BCG Hsp65 and HPV16 E7. Cell Stress Chaperones 5, 401–5.
Chu, N. R., Wu, H. B., Wu, T., Boux, L. J., Siegel, M. I. and Mizzen, L. A. (2000b) Immunotherapy of a human papillomavirus (HPV) type 16 E7-expressing tumour by administration of fusion protein comprising Mycobacterium bovis bacille Calmette-Guerin (BCG) hsp65 and HPV16 E7. Clin Exp Immunol 121, 216–25.
Cullinan, S. B. and Whitesell, L. (2006) Heat shock protein 90: a unique chemotherapeutic target. Semin Oncol 33, 457–65.
Elias, D., Markovits, D., Reshef, T., van der Zee, R. and Cohen, I. R. (1990) Induction and therapy of autoimmune diabetes in the non-obese diabetic (NOD/Lt) mouse by a 65-kDa heat shock protein. Proc Natl Acad Sci U S A 87, 1576–80.
Faure, O., Graff-Dubois, S., Bretaudeau, L., Derre, L., Gross, D. A., Alves, P. M., Cornet, S., Duffour, M. T., Chouaib, S., Miconnet, I., Gregoire, M., Jotereau, F., Lemonnier, F. A., Abastado, J. P. and Kosmatopoulos, K. (2004) Inducible Hsp70 as target of anticancer immunotherapy: identification of HLA-A*0201-restricted epitopes. Int J Cancer 108, 863–70.
Goetz, M. P., Toft, D., Reid, J., Ames, M., Stensgard, B., Safgren, S., Adjei, A. A., Sloan, J., Atherton, P., Vasile, V., Salazaar, S., Adjei, A., Croghan, G. and Erlichman, C. (2005) Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer. J Clin Oncol 23, 1078–87.
Gordon, N. F. and Clark, B. L. (2004) The challenges of bringing autologous HSP-based vaccines to commercial reality. Methods 32, 63–9.
Hartl, F. U. (1996) Molecular chaperones in cellular protein folding. Nature 381, 571–9.
Hauser, H., Shen, L., Gu, Q. L., Krueger, S. and Chen, S. Y. (2004) Secretory heat-shock protein as a dendritic cell-targeting molecule: a new strategy to enhance the potency of genetic vaccines. Gene Ther 11, 924–32.
Janetzki, S., Palla, D., Rosenhauer, V., Lochs, H., Lewis, J. J. and Srivastava, P. K. (2000) Immunization of cancer patients with autologous cancer-derived heat shock protein gp96 preparations: A pilot study. Int J Cancer 88, 232–8.
Jimbo, J., Sato, K., Hosoki, T., Shindo, M., Ikuta, K., Torimoto, Y. and Kohgo, Y. (2008) Induction of leukemia-specific antibodies by immunotherapy with leukemia-cell-derived heat shock protein 70. Cancer Sci 99, 1427–34.
Kamal, A., Thao, L., Sensintaffar, J., Zhang, L., Boehm, M. F., Fritz, L. C. and Burrows, F. J. (2003) A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 425, 407–10.
Kurotaki, T., Tamura, Y., Ueda, G., Oura, J., Kutomi, G., Hirohashi, Y., Sahara, H., Torigoe, T., Hiratsuka, H., Sunakawa, H., Hirata, K. and Sato, N. (2007) Efficient cross-presentation by heat shock protein 90-peptide complex-loaded dendritic cells via an endosomal pathway. J Immunol 179, 1803–13.
Lehner, T., Wang, Y., Whittall, T., McGowan, E., Kelly, C. G. and Singh, M. (2004) Functional domains of HSP70 stimulate generation of cytokines and chemokines, maturation of dendritic cells and adjuvanticity. Biochem Soc Trans 32, 629–32.
Li, Y., Subjeck, J., Yang, G., Repasky, E. and Wang, X. Y. (2006) Generation of anti-tumor immunity using mammalian heat shock protein 70 DNA vaccines for cancer immunotherapy. Vaccine 24, 5360–70.
Lindquist, S. and Craig, E. A. (1988) The heat-shock proteins. Annu Rev Genet 22, 631–77.
Liu, M. A. and Ulmer, J. B. (2005) Human clinical trials of plasmid DNA vaccines. Adv Genet 55, 25–40.
Liu, B., Ye, D., Song, X., Zhao, X., Yi, L., Song, J., Zhang, Z. and Zhao, Q. (2008) A novel therapeutic fusion protein vaccine by two different families of heat shock proteins linked with HPV16 E7 generates potent antitumor immunity and antiangiogenesis. Vaccine 26, 1387–96.
Maciag, P. C. and Paterson, Y. (2005) Technology evaluation: HspE7 (Stressgen). Curr Opin Mol Ther 7, 256–63.
Manjili, M. H., Henderson, R., Wang, X. Y., Chen, X., Li, Y., Repasky, E., Kazim, L. and Subjeck, J. R. (2002) Development of a recombinant HSP110-HER-2/neu vaccine using the chaperoning properties of HSP110. Cancer Res 62, 1737–42.
Manjili, M. H., Wang, X. Y., Chen, X., Martin, T., Repasky, E. A., Henderson, R. and Subjeck, J. R. (2003) HSP110-HER2/neu chaperone complex vaccine induces protective immunity against spontaneous mammary tumors in HER-2/neu transgenic mice. J Immunol 171, 4054–61.
Marcus, S. G., Choyke, P. L., Reiter, R., Jaffe, G. S., Alexander, R. B., Linehan, W. M., Rosenberg, S. A. and Walther, M. M. (1993) Regression of metastatic renal cell carcinoma after cytoreductive nephrectomy. J Urol 150, 463–6.
Mazzaferro, V., Coppa, J., Carrabba, M. G., Rivoltini, L., Schiavo, M., Regalia, E., Mariani, L., Camerini, T., Marchiano, A., Andreola, S., Camerini, R., Corsi, M., Lewis, J. J., Srivastava, P. K. and Parmiani, G. (2003) Vaccination with autologous tumor-derived heat-shock protein gp96 after liver resection for metastatic colorectal cancer. Clin Cancer Res 9, 3235–45.
Mori-Iwamoto, S., Kuramitsu, Y., Ryozawa, S., Mikuria, K., Fujimoto, M., Maehara, S., Maehara, Y., Okita, K., Nakamura, K. and Sakaida, I. (2007) Proteomics finding heat shock protein 27 as a biomarker for resistance of pancreatic cancer cells to gemcitabine. Int J Oncol 31, 1345–50.
Oki, Y., McLaughlin, P., Fayad, L. E., Pro, B., Mansfield, P. F., Clayman, G. L., Medeiros, L. J., Kwak, L. W., Srivastava, P. K. and Younes, A. (2007) Experience with heat shock protein-peptide complex 96 vaccine therapy in patients with indolent non-Hodgkin lymphoma. Cancer 109, 77–83.
Palladino, M. A., Jr., Srivastava, P. K., Oettgen, H. F. and DeLeo, A. B. (1987) Expression of a shared tumor-specific antigen by two chemically induced BALB/c sarcomas. Cancer Res 47, 5074–9.
Parmiani, G., Testori, A., Maio, M., Castelli, C., Rivoltini, L., Pilla, L., Belli, F., Mazzaferro, V., Coppa, J., Patuzzo, R., Sertoli, M. R., Hoos, A., Srivastava, P. K. and Santinami, M. (2004) Heat shock proteins and their use as anticancer vaccines. Clin Cancer Res 10, 8142–6.
Pockley, A. G. (2003) Heat shock proteins as regulators of the immune response. Lancet 362, 469–76.
Prakken, B. J., Roord, S., van Kooten, P. J., Wagenaar, J. P., van Eden, W., Albani, S. and Wauben, M. H. (2002) Inhibition of adjuvant-induced arthritis by interleukin-10-driven regulatory cells induced via nasal administration of a peptide analog of an arthritis-related heat-shock protein 60 T cell epitope. Arthritis Rheum 46, 1937–46.
Przepiorka, D. and Srivastava, P. K. (1998) Heat shock protein–peptide complexes as immunotherapy for human cancer. Mol Med Today 4, 478–84.
Puga Yung, G. L., Le, T. D., Roord, S., Prakken, B. and Albani, S. (2003) Heat shock proteins (HSP) for immunotherapy of rheumatoid arthritis (RA). Inflamm Res 52, 443–51.
Qian, J., Wang, S., Yang, J., Xie, J., Lin, P., Freeman, M. E., 3rd and Yi, Q. (2005) Targeting heat shock proteins for immunotherapy in multiple myeloma: generation of myeloma-specific CTLs using dendritic cells pulsed with tumor-derived gp96. Clin Cancer Res 11, 8808–15.
Ragno, S., Winrow, V. R., Mascagni, P., Lucietto, P., Di Pierro, F., Morris, C. J. and Blake, D. R. (1996) A synthetic 10-kD heat shock protein (hsp10) from Mycobacterium tuberculosis modulates adjuvant arthritis. Clin Exp Immunol 103, 384–90.
Raska, M. and Weigl, E. (2005) Heat shock proteins in autoimmune diseases. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 149, 243–9.
Ren, W., Strube, R., Zhang, X., Chen, S. Y. and Huang, X. F. (2004) Potent tumor-specific immunity induced by an in vivo heat shock protein-suicide gene-based tumor vaccine. Cancer Res 64, 6645–51.
Rigano, R., Profumo, E., Buttari, B., Tagliani, A., Petrone, L., D’Amati, G., Ippoliti, F., Capoano, R., Fumagalli, L., Salvati, B. and Businaro, R. (2007) Heat shock proteins and autoimmunity in patients with carotid atherosclerosis. Ann N Y Acad Sci 1107, 1–10.
Rossini, A. A., Mordes, J. P. and Like, A. A. (1985) Immunology of insulin-dependent diabetes mellitus. Annu Rev Immunol 3, 289–320.
Sato, K., Torimoto, Y., Tamura, Y., Shindo, M., Shinzaki, H., Hirai, K. and Kohgo, Y. (2001) Immunotherapy using heat-shock protein preparations of leukemia cells after syngeneic bone marrow transplantation in mice. Blood 98, 1852–7.
Schirmbeck, R., Riedl, P., Kupferschmitt, M., Wegenka, U., Hauser, H., Rice, J., Kroger, A. and Reimann, J. (2006) Priming protective CD8 T cell immunity by DNA vaccines encoding chimeric, stress protein-capturing tumor-associated antigen. J Immunol 177, 1534–42.
Sharp, S. and Workman, P. (2006) Inhibitors of the HSP90 molecular chaperone: current status. Adv Cancer Res 95, 323–48.
Shimada, A., Kasatani, T., Takei, I., Maruyama, T., Nomaguchi, H., Ozawa, Y., Ishii, M., Kasuga, A., Tashiro, F., Miyazaki, J., Yamamura, K. and Saruta, T. (1996) Immune response to heat-shock protein correlates with induction of insulitis in I-E alpha d transgenic NOD mice. Diabetes 45, 165–9.
Solit, D. B., Osman, I., Polsky, D., Panageas, K. S., Daud, A., Goydos, J. S., Teitcher, J., Wolchok, J. D., Germino, F. J., Krown, S. E., Coit, D., Rosen, N. and Chapman, P. B. (2008) Phase II trial of 17-allylamino-17-demethoxygeldanamycin in patients with metastatic melanoma. Clin Cancer Res 14, 8302–7.
Srivastava, P. (2002) Interaction of heat shock proteins with peptides and antigen presenting cells: chaperoning of the innate and adaptive immune responses. Annu Rev Immunol 20, 395–425.
Srivastava, P. K. (2006) Therapeutic cancer vaccines. Curr Opin Immunol 18, 201–5.
Srivastava, P. K. and Das, M. R. (1984) The serologically unique cell surface antigen of Zajdela ascitic hepatoma is also its tumor-associated transplantation antigen. Int J Cancer 33, 417–22.
Srivastava, P. K., DeLeo, A. B. and Old, L. J. (1986) Tumor rejection antigens of chemically induced sarcomas of inbred mice. Proc Natl Acad Sci U S A 83, 3407–11.
Srivastava, P. K., Udono, H., Blachere, N. E. and Li, Z. (1994) Heat shock proteins transfer peptides during antigen processing and CTL priming. Immunogenetics 39, 93–8.
Suzue, K., Zhou, X., Eisen, H. N. and Young, R. A. (1997) Heat shock fusion proteins as vehicles for antigen delivery into the major histocompatibility complex class I presentation pathway. Proc Natl Acad Sci U S A 94, 13146–51.
Takakura, Y., Takemoto, S. and Nishikawa, M. (2007) Hsp-based tumor vaccines: state-of-the-art and future directions. Curr Opin Mol Ther 9, 385–91.
Tamura, Y., Peng, P., Liu, K., Daou, M. and Srivastava, P. K. (1997) Immunotherapy of tumors with autologous tumor-derived heat shock protein preparations. Science 278, 117–20.
Tsutsumi, S. and Neckers, L. (2007) Extracellular heat shock protein 90: a role for a molecular chaperone in cell motility and cancer metastasis. Cancer Sci 98, 1536–9.
Udono, H. and Srivastava, P. K. (1993) Heat shock protein 70-associated peptides elicit specific cancer immunity. J Exp Med 178, 1391–6.
Udono, H. and Srivastava, P. K. (1994) Comparison of tumor-specific immunogenicities of stress-induced proteins gp96, hsp90, and hsp70. J Immunol 152, 5398–403.
van Puijvelde, G. H., van Es, T., van Wanrooij, E. J., Habets, K. L., de Vos, P., van der Zee, R., van Eden, W., van Berkel, T. J. and Kuiper, J. (2007) Induction of oral tolerance to HSP60 or an HSP60-peptide activates T cell regulation and reduces atherosclerosis. Arterioscler Thromb Vasc Biol 27, 2677–83.
Wang, X. Y., Chen, X., Manjili, M. H., Repasky, E., Henderson, R. and Subjeck, J. R. (2003) Targeted immunotherapy using reconstituted chaperone complexes of heat shock protein 110 and melanoma-associated antigen gp100. Cancer Res 63, 2553–60.
Wang, X. Y., Kazim, L., Repasky, E. A. and Subjeck, J. R. (2001) Characterization of heat shock protein 110 and glucose-regulated protein 170 as cancer vaccines and the effect of fever-range hyperthermia on vaccine activity. J Immunol 166, 490–7.
Wang, Y., Kelly, C. G., Singh, M., McGowan, E. G., Carrara, A. S., Bergmeier, L. A. and Lehner, T. (2002) Stimulation of Th1-polarizing cytokines, C-C chemokines, maturation of dendritic cells, and adjuvant function by the peptide binding fragment of heat shock protein 70. J Immunol 169, 2422–9.
Wang, H. H., Mao, C. Y., Teng, L. S. and Cao, J. (2006) Recent advances in heat shock protein-based cancer vaccines. Hepatobiliary Pancreat Dis Int 5, 22–7.
Wegele, H., Muller, L. and Buchner, J. (2004) Hsp70 and Hsp90–a relay team for protein folding. Rev Physiol Biochem Pharmacol 151, 1–44.
Wendling, U., Paul, L., van der Zee, R., Prakken, B., Singh, M. and van Eden, W. (2000) A conserved mycobacterial heat shock protein (hsp) 70 sequence prevents adjuvant arthritis upon nasal administration and induces IL-10-producing T cells that cross-react with the mammalian self-hsp70 homologue. J Immunol 164, 2711–7.
Whitesell, L., Mimnaugh, E. G., De Costa, B., Myers, C. E. and Neckers, L. M. (1994) Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. Proc Natl Acad Sci U S A 91, 8324–8.
Xu, Q., Schett, G., Seitz, C. S., Hu, Y., Gupta, R. S. and Wick, G. (1994) Surface staining and cytotoxic activity of heat-shock protein 60 antibody in stressed aortic endothelial cells. Circ Res 75, 1078–85.
Acknowledgements
This work was supported in part by a grant from the National Institutes of Health grant RO1CA91889, institutional support from Scott & White Memorial Hospital and Clinic, Texas A&M University System Health Science Center College of Medicine, the Central Texas Veterans Health Administration and an Endowment from the Cain Foundation (to A. A.).
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2010 Springer Science+Business Media B.V.
About this chapter
Cite this chapter
Zheng, H., Asea, A. (2010). Heat Shock Protein (HSP)-Based Immunotherapies. In: Asea, A., Pedersen, B. (eds) Heat Shock Proteins and Whole Body Physiology. Heat Shock Proteins, vol 5. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-3381-9_8
Download citation
DOI: https://doi.org/10.1007/978-90-481-3381-9_8
Published:
Publisher Name: Springer, Dordrecht
Print ISBN: 978-90-481-3380-2
Online ISBN: 978-90-481-3381-9
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)