Cancer Immunology, Immunotherapy

, Volume 55, Issue 3, pp 320–328 | Cite as

Cancer immunotherapy based on intracellular hyperthermia using magnetite nanoparticles: a novel concept of “heat-controlled necrosis” with heat shock protein expression

Symposium in Writing


Heat shock proteins (HSPs) are highly conserved proteins whose syntheses are induced by a variety of stresses, including heat stress. Since the expression of HSPs, including HSP70, protects cells from heat-induced apoptosis, HSP expression has been considered to be a complicating factor in hyperthermia. On the other hand, recent reports have shown the importance of HSPs, such as HSP70, HSP90 and glucose-regulated protein 96 (gp96), in immune reactions. If HSP expression induced by hyperthermia is involved in tumor immunity, novel cancer immunotherapy based on this novel concept can be developed. In such a strategy, a tumor-specific hyperthermia system, which can heat the local tumor region to the intended temperature without damaging normal tissue, would be highly advantageous. To achieve tumor-specific hyperthermia, we have developed an intracellular hyperthermia system using magnetite nanoparticles. This novel hyperthermia system can induce necrotic cell death via HSP expression, which induces antitumor immunity. In the present article, cancer immunology and immunotherapy based on hyperthermia, and HSP expression are reviewed and discussed.


Heat shock proteins Hyperthermia Tumor immunity Magnetite Glioma Melanoma 



This work was partly supported by Grants-in-Aid for Scientific Research (No. 13853005), University Start-Ups Creation Support System, and the twenty-first century COE Program “Nature-Guided Materials Processing” from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.


  1. 1.
    Asea A, Kraeft SK, Kurt-Jones EA, Stevenson MA, Chen LB, Finberg RW, Koo GC, Calderwood SK (2000) HSP70 stimulates cytokine production through a CD14-dependent pathway, demonstrating its dual role as a chaperon and cytokine. Nat Med 6:435–442PubMedCrossRefGoogle Scholar
  2. 2.
    Basu S, Binder R, Suto R, Anderson KM, Srivastava PK (2000) Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NFkB pathway. Int Immunol 12:1539–1546PubMedCrossRefGoogle Scholar
  3. 3.
    Becker T, Hartl FU, Wieland F (2002) CD40, an extracellular receptor for binding and uptake of Hsp70-peptide complexes. J Cell Biol 158:1277–1285PubMedCrossRefGoogle Scholar
  4. 4.
    Belli F, Testori A, Rivoltini L, Maio M, Andreola G, Sertoli MR, 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 JJ, Srivastava P, 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 20:4169–4180PubMedCrossRefGoogle Scholar
  5. 5.
    Castelli C, Rivoltini L, Rini F, Belli F, Testori A, Maio M, Mazzaferro V, Coppa J, Srivastava PK, Parmiani G (2004) Heat shock proteins: biological functions and clinical application as personalized vaccines for human cancer. Cancer Immunol Immunother 53:227–233PubMedCrossRefGoogle Scholar
  6. 6.
    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 16:615–624PubMedCrossRefGoogle Scholar
  7. 7.
    Dewey WC, Hopwood LE, Sapareto LA, Gerweck LE (1977) Cellular responses to combinations of hyperthermia and radiation. Radiology 123:463–474PubMedGoogle Scholar
  8. 8.
    Dressel R, Lubbers M, Walter L, Herr W, Gunther E (1999) Enhanced susceptibility to cytotoxic T lymphocytes without increase of MHC class I antigen expression after conditional overexpression of heat shock protein 70 in target cells. Eur J Immunol 29:3925–3935PubMedCrossRefGoogle Scholar
  9. 9.
    Garnett CT, Palena C, Chakarborty M, Tsang KY, Schlom J, Hodge JW (2004) Sublethal irradiation of human tumor cells modulates phenotype resulting in enhanced killing by cytotoxic T lymphocytes. Cancer Res 64:7985–7994PubMedCrossRefGoogle Scholar
  10. 10.
    Gordon RT, Hines JR, Gordon D (1979) Intracellular hyperthermia. A biophysical approach to cancer treatment via intracellular temperature and biophysical alterations. Med Hypothesis 5:83–102CrossRefGoogle Scholar
  11. 11.
    Hauser H, Shen L, Gu QL, Krueger S, Chen SY (2004) Secretory heat-shock protein as a dendritic cell-targeting molecule: a new strategy to enhance the potency of genetic vaccines. Gene Ther 11:924–932PubMedCrossRefGoogle Scholar
  12. 12.
    Ito A, Tanaka K, Honda H, Abe S, Yamaguchi H, Kobayashi T (2003) Complete regression of mouse mammary carcinoma with a size greater than 15 mm by frequent repeated hyperthermia using magnetite nanoparticles. J Biosci Bioeng 96:364–369PubMedGoogle Scholar
  13. 13.
    Ito A, Shinkai M, Honda H, Wakabayashi T, Yoshida J, Kobayashi T (2001) Augmentation of MHC class I antigen presentation via heat shock protein expression by hyperthermia. Cancer Immunol Immunother 50:515–522PubMedCrossRefGoogle Scholar
  14. 14.
    Ito A, Shinkai M, Honda H, Yoshikawa K, Saga S, Wakabayashi T, Yoshida J, Kobayashi T (2003) Heat shock protein 70 expression induces antitumor immunity during intracellular hyperthermia using magnetite nanoparticles. Cancer Immunol Immunother 52:80–88PubMedGoogle Scholar
  15. 15.
    Ito A, Kuga Y, Honda H, Kikkawa H, Horiuchi A, Watanabe Y, Kobayashi T (2004) Magnetite nanoparticle-loaded anti-HER2 immunoliposomes for combination of antibody therapy with hyperthermia. Cancer Lett 212:167–175PubMedCrossRefGoogle Scholar
  16. 16.
    Ito A, Tanaka K, Kondo K, Shinkai M, Honda H, Matsumoto K, Saida T, Kobayashi T (2003) Tumor regression by combined immunotherapy and hyperthermia using magnetic nanoparticles in an experimental subcutaneous murine melanoma. Cancer Sci 94:308–313PubMedCrossRefGoogle Scholar
  17. 17.
    Ito A, Shinkai M, Honda H, Kobayashi T (2001) Heat-inducible TNF-alpha gene therapy combined with hyperthermia using magnetic nanoparticles as a novel tumor-targeted therapy. Cancer Gene Ther 8:649–654PubMedCrossRefGoogle Scholar
  18. 18.
    Ito A, Matsuoka M, Honda H, Kobayashi T (2004) Anititumor effects of combined therapy of recombinant heat shock protein 70 and hyperthermia using magnetic nanoparticles in an experimental subcutaneous murine melanoma. Cancer Immunol Immunother 53:26–32PubMedCrossRefGoogle Scholar
  19. 19.
    Ito A, Matsuoka M, Honda H, Kobayashi T (2003) Heat shock protein 70 gene therapy combined with hyperthermia using magnetic nanoparticles. Cancer Gene Ther 10:918–925PubMedCrossRefGoogle Scholar
  20. 20.
    Jordan A, Wust P, Fähling H, John W, Hinz A, Felix R (1993) Inductive heating of ferrimagnetic particles and magnetic fluids: physical evaluation of their potential for hyperthermia. Int J Hyperthermia 9:51–68PubMedCrossRefGoogle Scholar
  21. 21.
    Jordan A, Wust P, Scholz R, Tesch B, Fähling H, Mitrovics T, Vogl T, Cervós-Navarro J, Felix R (1996) Cellular uptake of magnetic fluid particles and their effects on human adenocarcinoma cells exposed to AC magnetic fields in vitro. Int J Hyperthermia 12:705–722PubMedCrossRefGoogle Scholar
  22. 22.
    Kato N, Kobayashi T, Honda H (2003) Screening of stress enhancer based on analysis of gene expression profiles: enhancement of hyperthermia-induced tumor necrosis by an MMP-3 inhibitor. Cancer Sci 94:644–649PubMedCrossRefGoogle Scholar
  23. 23.
    Labarriere N, Bretaudeau L, Gervois N, Bodinier M, Bougras G, Diez E, Lang F, Gregoire M, Jotereau F (2002) Apoptotic body-loaded dendritic cells efficiently cross-prime cytotoxic T lymphocytes specific for NA17-A antigen but not for Melan-A/MART-1 antigen. Int J Cancer 101:280–286PubMedCrossRefGoogle Scholar
  24. 24.
    Le B, Shinkai M, Kitade T, Honda H, Yoshida J, Wakabayashi T, Kobayashi T (2001) Preparation of tumor-specific magnetoliposomes and their application for hyperthermia. J Chem Eng Jpn 34:66–72CrossRefGoogle Scholar
  25. 25.
    Lindquist S (1986) The heat-shock response. Annu Rev Biochem 55:1151–1191PubMedCrossRefGoogle Scholar
  26. 26.
    Massa C, Guiducci C, Arioli I, Parenza M, Colombo MP, Melani C (2004) Enhanced efficacy of tumor cell vaccines transfected with secretable hsp70. Cancer Res 64:1502–1508PubMedCrossRefGoogle Scholar
  27. 27.
    Matsuoka F, Shinkai M, Honda H, Kubo T, Sugita T, Kobayashi T (2004) Hyperthermia using magnetite cationic liposomes for hamster osteosarcoma. Biomagn Res Technol 2:3PubMedCrossRefGoogle Scholar
  28. 28.
    Matsuno H, Tohnai I, Mitsudo K, Hayashi Y, Ito M, Shinkai M, Kobayashi T, Yoshida J, Ueda M (2001) Interstitial hyperthermia using magnetite cationic liposomes inhibit to tumor growth of VX-7 transplanted tumor in rabbit tongue. Jpn J Hyperthermic Oncol 17:141–149Google Scholar
  29. 29.
    Mazzaferro V, Coppa J, Carrabba MG, Rivoltini L, Schiavo M, Regalia E, Mariani L, Camerini T, Marchiano A, Andreola S, Camerini R, Corsi M, Lewis JJ, Srivastava PK, Parmiani G (2003) Vaccination with autologous tumor-derived heat-shock protein gp96 after liver resection for metastatic colorectal cancer. Clin Cancer Res 9:3235–3245PubMedGoogle Scholar
  30. 30.
    Ménoret A, Chandawarkar R (1998) Heat-shock protein-based anticancer immunotherapy: an idea whose time has come. Sem Immunol 25:654–660Google Scholar
  31. 31.
    Milani V, Noessner E, Ghose S, Kuppner M, Ahrens B, Scharner A, Gastpar R, Issels RD (2002) Heat shock protein 70: role in antigen presentation and immune stimulation. Int J Hyperthermia 18:563–575PubMedCrossRefGoogle Scholar
  32. 32.
    Moroz P, Jones SK, Gray BN (2002) Magnetically mediated hyperthermia: current status and future directions. Int J Hyperthermia 18:267–284PubMedCrossRefGoogle Scholar
  33. 33.
    Mosser DD, Caron AW, Bourget L, Meriin AB, Sherman MY, Morimoto RI, Massie B (2000) The chaperon function of hsp 70 is required for protection against stress-induced apoptosis. Mol Cell Biol 20:7146–7159PubMedCrossRefGoogle Scholar
  34. 34.
    Shinkai M, Yanase M, Honda H, Wakabayashi T, Yoshida J, Kobayashi T (1996) Intracellular hyperthermia for cancer using magnetite cationic liposome: in vitro study. Jpn J Cancer Res 87:1179–1183PubMedGoogle Scholar
  35. 35.
    Shinkai M, Le B, Honda H, Yoshikawa K, Shimizu K, Saga S, Wakabayashi T, Yoshida J, Kobayashi T (2001) Targeting hyperthermia for renal cell carcinoma using human MN antigen-specific magnetoliposomes. Jpn J Cancer Res 92:1138–1145PubMedGoogle Scholar
  36. 36.
    Srivastava PK, Ménoret A, Basu S, Binder R, Quade K (1998) Heat shock proteins come of age: primitive functions acquired new roles in an adaptive world. Immunity 8:657–665PubMedCrossRefGoogle Scholar
  37. 37.
    Srivastava PK, Maki RG (1991) Stress-induced proteins in immune response to cancer. Curr Top Microbiol Immunol 167:109–123PubMedGoogle Scholar
  38. 38.
    Srivastava PK, Heike M (1993) Tumor-specific immunogenicity of stress-induced proteins: convergence of two evolutionary pathways of antigen presentation? Semin Immunol 3:57–64Google Scholar
  39. 39.
    Srivastava PK, Udono H, Blachere NE, Li Z (1994) Heat shock proteins transfer peptides during antigen processing and CTL priming. Immunogenetics 39:93–98PubMedCrossRefGoogle Scholar
  40. 40.
    Srivastava PK (2002) Roles of heat-shock proteins in innate and adaptive immunity. Nat Rev Immunol 2:185–194PubMedCrossRefGoogle Scholar
  41. 41.
    Srivastava PK (2002) Interaction of heat shock proteins with peptides and antigen presenting cells: chaperoning of the innate and adaptive immune responses. Annu Rev Immunol 20:395–425PubMedCrossRefGoogle Scholar
  42. 42.
    Subjeck JR, Sciandra JJ, Chao CF, Johnson RJ (1982) Heat shock proteins and biological response to hyperthermia. Br J Cancer 45:127–131Google Scholar
  43. 43.
    Subjeck JR, Sciandra JJ, Johnson RJ (1982) Heat shock proteins and thermotolerance; a comparison of induction kinetics. Br J Radiol 55:579–584PubMedCrossRefGoogle Scholar
  44. 44.
    Suzuki M, Shinkai M, Honda H, Kobayashi T (2003) Anticancer effect and immune induction by hyperthermia of malignant melanoma using magnetite cationic liposomes. Melanoma Res 13:129–135PubMedCrossRefGoogle Scholar
  45. 45.
    Tanaka A, Ito A, Kobayashi T, Kawamura T, Shimada S, Matsumoto K, Saida T, Honda H (2005) Intratumoral injection of immature dendritic cells enhances antitumor effect of hyperthermia using magnetic nanoparticles. Int J Cancer 116:624–633PubMedCrossRefGoogle Scholar
  46. 46.
    Tanaka A, Ito A, Kobayashi T, Kawamura T, Shimada S, Matsumoto K, Saida T, Honda H (2005) Heat immunotherapy using magnetic nanoparticles and dendritic cells for T-lymphoma. J Bio Bioeng 100:112–115PubMedCrossRefGoogle Scholar
  47. 47.
    Todryk S, Melcher AA, Hardwick N, Linardakis E, Bateman A, Colombo MP, Stoppacciaro A, Vile RG (1999) Heat shock protein 70 induced during tumor cell killing induces Th1 cytokines and targets immature dendritic cell precursors to enhance antigen uptake. J Immunol 163:1398–1408PubMedGoogle Scholar
  48. 48.
    Udono H, Srivastava PK (1994) Comparison of tumor-specific immunogenicities of stress-induced protein gp96, hsp90, and hsp70. J Immunol 152:5398–5403PubMedGoogle Scholar
  49. 49.
    Van der Zee J (2002) Heating the patient: a promising approach? Annu Oncol 13:1173–1184CrossRefGoogle Scholar
  50. 50.
    Wells AD, Rai SK, Salvato MS, Band H, Malkovsky M (1998) Hsp72-mediated augmentation of MHC class I surface expression and endogenous antigen presentation. Int Immunol 10:609–617PubMedCrossRefGoogle Scholar
  51. 51.
    Wells AD, Malkovsky M (2000) Heat shock proteins, tumor immunogenicity and antigen presentation: an integrated view. Immunol Today 21:129–132PubMedCrossRefGoogle Scholar
  52. 52.
    Yanase M, Shinkai M, Honda H, Wakabayashi T, Yoshida J, Kobayashi T (1998) Intracellular hyperthermia for cancer using magnetite cationic liposome: an in vivo study. Jpn J Cancer Res 89:463–469PubMedGoogle Scholar
  53. 53.
    Yanase M, Shinkai M, Honda H, Wakabayashi T, Yoshida J, Kobayashi T (1998) Antitumor immunity induction by intracellular hyperthermia using magnetite cationic liposomes. Jpn J Cancer Res 89:775–782PubMedGoogle Scholar
  54. 54.
    Ye J, Chen GS, Song HP, Li ZS, Huang YY, Qu P, Sun YJ, Zhang XM, Sui YF (2004) Heat shock protein 70/MAGE-1 tumor vaccine can enhance the potency of MAGE-1-specific cellular immune responses in vivo. Cancer Immunol Immunother 53:825–834PubMedCrossRefGoogle Scholar
  55. 55.
    Yonezawa M, Ohtsuka T, Matsui N, Tsuji H, Kato KH, Moriyama A, Kato T (1996) Hyperthermia induces apoptosis in malignant fibrous histiocytoma cells in vitro. Int J Cancer 66:347–351PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  1. 1.Department of Biotechnology, School of EngineeringNagoya UniversityNagoyaJapan
  2. 2.School of Bioscience and BiotechnologyChubu UniversityAichiJapan

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