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Diverse immune mechanisms may contribute to the survival benefit seen in cancer patients receiving hyperthermia

Abstract

There is increasing documentation of significant survival benefits achieved in cancer patients treated with hyperthermia in combination with radiation and/or chemotherapy. Most evidence collected regarding the mechanisms by which hyperthermia positively influences tumor control has centered on in vitro data showing the ability of heat shock temperatures (usually above 42°C) to result in radio- or chemosensitization. However, these high temperatures are difficult to achieve in vivo, and new thermometry data in patients reveal that much of the tumor and surrounding region is only heated to 40–41°C or less as a result of vascular drainage from the target zone of the heated tumor. Thus, there is now a growing appreciation of a role for mild hyperthermia in the stimulation of various arms of the immune system in contributing to long term protection from tumor growth. Indeed, a review of recent literature suggests the existence of an array of thermally sensitive functions which may exist naturally to help the organism to establish a new “set point” of immune responsiveness during fever. This review summarizes recent literature identifying complex effects of temperature on immune cells and potential cellular mechanisms by which increased temperature may enhance immune surveillance.

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References

  1. Valdagni R, Amichetti M. Report of long-term follow-up in a randomized trial comparing radiation therapy and radiation therapy plus hyperthermia to metastatic lymph nodes in stage IV head and neck patients. Int J Radiat Oncol Biol Phys. 1994;28(1):163–9.

    PubMed  CAS  Google Scholar 

  2. Overgaard J, et al. Randomised trial of hyperthermia as adjuvant to radiotherapy for recurrent or metastatic malignant melanoma. European society for hyperthermic oncology. Lancet. 1995;345(8949):540–3.

    Article  PubMed  CAS  Google Scholar 

  3. Sugimachi K, et al. Hyperthermia combined with chemotherapy and irradiation for patients with carcinoma of the oesophagus—a prospective randomized trial. Int J Hyperthermia. 1992;8(3):289–95.

    Article  PubMed  CAS  Google Scholar 

  4. Sugimachi K, et al. Chemotherapy combined with or without hyperthermia for patients with oesophageal carcinoma: a prospective randomized trial. Int J Hyperthermia. 1994;10(4):485–93.

    Article  PubMed  CAS  Google Scholar 

  5. van der Zee J, et al. Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: a prospective, randomised, multicentre trial. Dutch Deep Hyperthermia Group. Lancet. 2000;355(9210):1119–25.

    Article  PubMed  Google Scholar 

  6. Sneed PK, et al. Survival benefit of hyperthermia in a prospective randomized trial of brachytherapy boost ± hyperthermia for glioblastoma multiforme. Int J Radiat Oncol Biol Phys. 1998;40(2):287–95.

    PubMed  CAS  Google Scholar 

  7. Vernon CC, et al. Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: results from five randomized controlled trials. International Collaborative Hyperthermia Group. Int J Radiat Oncol Biol Phys. 1996;35(4):731–44.

    PubMed  CAS  Google Scholar 

  8. Jones EL, et al. Randomized trial of hyperthermia and radiation for superficial tumors. J Clin Oncol. 2005;23(13):3079–85.

    Article  PubMed  Google Scholar 

  9. Corry PM, Armour EP. The heat shock response: role in radiation biology and cancer therapy. Int J Hyperthermia. 2005;21(8):769–78.

    Article  PubMed  Google Scholar 

  10. Iliakis G, Wu W, Wang M. DNA double strand break repair inhibition as a cause of heat radiosensitization: re-evaluation considering backup pathways of NHEJ. Int J Hyperthermia. 2008;24(1):17–29.

    Article  PubMed  CAS  Google Scholar 

  11. Xu Y, et al. Fever-range whole body hyperthermia increases the number of perfused tumor blood vessels and therapeutic efficacy of liposomally encapsulated doxorubicin. Int J Hyperthermia. 2007;23(6):513–27.

    Article  PubMed  CAS  Google Scholar 

  12. Souslova T, Averill-Bates DA. Multidrug-resistant hela cells overexpressing MRP1 exhibit sensitivity to cell killing by hyperthermia: interactions with etoposide. Int J Radiat Oncol Biol Phys. 2004;60(5):1538–51.

    PubMed  CAS  Google Scholar 

  13. Di YP, et al. Hsp70 translocates into a cytoplasmic aggregate during lymphocyte activation. J Cell Physiol. 1995;165(2):228–38.

    Article  PubMed  CAS  Google Scholar 

  14. Di YP, Repasky EA, Subjeck JR. Distribution of HSP70, protein kinase C, and spectrin is altered in lymphocytes during a fever-like hyperthermia exposure. J Cell Physiol. 1997;172(1):44–54.

    Article  PubMed  CAS  Google Scholar 

  15. Burd R, et al. Tumor cell apoptosis, lymphocyte recruitment and tumor vascular changes are induced by low temperature, long duration (fever-like) whole body hyperthermia. J Cell Physiol. 1998;177(1):137–47.

    Article  PubMed  CAS  Google Scholar 

  16. Wang WC, et al. Fever-range hyperthermia enhances L-selectin-dependent adhesion of lymphocytes to vascular endothelium. J Immunol. 1998;160(2):961–9.

    PubMed  CAS  Google Scholar 

  17. Ostberg JR, et al. Enhancement of natural killer (NK) cell cytotoxicity by fever-range thermal stress is dependent on NKG2D function and is associated with plasma membrane NKG2D clustering and increased expression of MICA on target cells. J Leukoc Biol. 2007;82(5):1322–31.

    Article  PubMed  CAS  Google Scholar 

  18. Hasday JD, Fairchild KD, Shanholtz C. The role of fever in the infected host. Microbes Infect. 2000;2(15):1891–904.

    Article  PubMed  CAS  Google Scholar 

  19. Mackowiak PA, et al. Concepts of fever: recent advances and lingering dogma. Clin Infect Dis. 1997;25(1):119–38.

    Article  PubMed  CAS  Google Scholar 

  20. Kluger MJ, Ringler DH, Anver MR. Fever and survival. Science. 1975;188(4184):166–8.

    Article  PubMed  CAS  Google Scholar 

  21. Commission IT. Glossary of terms of thermal physiology. Third Edition. Jpn J Physiol. 2001;51:245–80.

    Google Scholar 

  22. Gordon C. Temperature regulation in the laboratory rodent. New York: Cambridge University Press; 1993.

    Google Scholar 

  23. Jiang Q, et al. Febrile core temperature is essential for optimal host defense in bacterial peritonitis. Infect Immun. 2000;68(3):1265–70.

    Article  PubMed  CAS  Google Scholar 

  24. Wiemann B, Starnes CO. Coley’s toxins, tumor necrosis factor and cancer research: a historical perspective. Pharmacol Ther. 1994;64(3):529–64.

    Article  PubMed  CAS  Google Scholar 

  25. Nauts HC, McLaren JR. Coley toxins—the first century. Adv Exp Med Biol. 1990;267:483–500.

    PubMed  CAS  Google Scholar 

  26. Sakamoto J, Satoshi T, Watanabe Y, Hayata Y, Okayasu T, Nakazato H, et al. Meta-analysis of adjuvant immunochemotherapy using OK-432 in patients with resected non-small-cell lung cancer. J Immunother. 2001;24(3):250–6.

    Article  CAS  Google Scholar 

  27. Hobohm U. Fever and cancer in perspective. Cancer Immunol Immunother. 2001;50(8):391–6.

    PubMed  CAS  Google Scholar 

  28. Brizel DM, et al. Radiation therapy and hyperthermia improve the oxygenation of human soft tissue sarcomas. Cancer Res. 1996;56(23):5347–50.

    PubMed  CAS  Google Scholar 

  29. Kappel M, et al. Effects of in vitro hyperthermia on the proliferative response of blood mononuclear cell subsets, and detection of interleukins 1 and 6, tumour necrosis factor-alpha and interferon-gamma. Immunology. 1991;73(3):304–8.

    PubMed  CAS  Google Scholar 

  30. Ozawa H, Matsuda T, Iwaguchi T. Whole-body hyperthermia maintains the secondary immune response of specific antitumour immune T cells. Int J Hyperthermia. 1991;7(1):125–30.

    Article  PubMed  CAS  Google Scholar 

  31. Ostberg JR, et al. Regulatory potential of fever-range whole body hyperthermia on Langerhans cells and lymphocytes in an antigen-dependent cellular immune response. J Immunol. 2001;167(5):2666–70.

    PubMed  CAS  Google Scholar 

  32. Evans SS, et al. Fever-range hyperthermia dynamically regulates lymphocyte delivery to high endothelial venules. Blood. 2001;97(9):2727–33.

    Article  PubMed  CAS  Google Scholar 

  33. Hatzfeld-Charbonnier AS, et al. Influence of heat stress on human monocyte-derived dendritic cell functions with immunotherapeutic potential for antitumor vaccines. J Leukoc Biol. 2007;81(5):1179–87.

    Article  PubMed  CAS  Google Scholar 

  34. Harris JW, Meneses JJ. Effects of hyperthermia on the production and activity of primary and secondary cytolytic T-lymphocytes in vitro. Cancer Res. 1978;38(4):1120–6.

    PubMed  CAS  Google Scholar 

  35. Roberts NJ Jr, Sandberg K. Hyperthermia and human leukocyte function: II. Enhanced production of and response to leukocyte migration inhibition factor (LIF). J Immunol. 1993;122:1990–3.

    Google Scholar 

  36. Koga S, et al. The effects of total-body hyperthermia combined with anticancer drugs on immunity in advanced cancer patients. Cancer. 1983;52(7):1173–7.

    Article  PubMed  CAS  Google Scholar 

  37. Shen RN, et al. Influence of elevated temperature on natural killer cell activity, lymphokine-activated killer cell activity and lectin-dependent cytotoxicity of human umbilical cord blood and adult blood cells. Int J Radiat Oncol Biol Phys. 1994;29(4):821–6.

    PubMed  CAS  Google Scholar 

  38. Choi M, et al. Short-term heat exposure inhibits inflammation by abrogating recruitment of and nuclear factor-{kappa}B activation in neutrophils exposed to chemotactic cytokines. Am J Pathol. 2008;172:367–777.

    Article  PubMed  CAS  Google Scholar 

  39. Rice P, et al. Febrile-range hyperthermia augments neutrophil accumulation and enhances lung injury in experimental gram-negative bacterial pneumonia. J Immunol. 2005;174(6):3676–85.

    PubMed  CAS  Google Scholar 

  40. Grabbe S, Schwarz T. Immunoregulatory mechanisms involved in elicitation of allergic contact hypersensitivity. Immunol Today. 1998;19(1):37–44.

    Article  PubMed  CAS  Google Scholar 

  41. Ostberg JR, Patel R, Repasky EA. Regulation of immune activity by mild (fever-range) whole body hyperthermia: effects on epidermal Langerhans cells. Cell Stress Chaper. 2000;5(5):458–61.

    Article  CAS  Google Scholar 

  42. Ostberg JR, Kabingu E, Repasky EA. Thermal regulation of dendritic cell activation and migration from skin explants. Int J Hyperthermia. 2003;19(5):520–33.

    Article  PubMed  CAS  Google Scholar 

  43. Peng JC, et al. Monocyte-derived DC primed with TLR agonists secrete IL-12p70 in a CD40-dependent manner under hyperthermic conditions. J Immunother. 2006;29(6):606–15.

    Article  PubMed  CAS  Google Scholar 

  44. Tournier JN, et al. Fever-like thermal conditions regulate the activation of maturing dendritic cells. J Leukoc Biol. 2003;73(4):493–501.

    Article  PubMed  CAS  Google Scholar 

  45. Evans SS, et al. Dynamic association of L-selectin with the lymphocyte cytoskeletal matrix. J Immunol. 1999;162(6):3615–24.

    PubMed  CAS  Google Scholar 

  46. Rescigno M, Granucci F, Ricciardi-Castagnoli P. Molecular events of bacterial-induced maturation of dendritic cells. J Clin Immunol. 2000;20(3):161–6.

    Article  PubMed  CAS  Google Scholar 

  47. Ensor JE, et al. Differential effects of hyperthermia on macrophage interleukin-6 and tumor necrosis factor-alpha expression. Am J Physiol. 1994;96(4 Pt 1):C967–74.

    Google Scholar 

  48. Ensor JE, Crawford EK, Hasday JD. Warming macrophages to febrile range destabilizes tumor necrosis factor-alpha mRNA without inducing heat shock. Am J Physiol. 1995;269(5 Pt 1):C1140–6.

    PubMed  CAS  Google Scholar 

  49. Moser M, Murphy KM. Dendritic cell regulation of TH1-TH2 development. Nat Immunol. 2000;1(3):199–205.

    Article  PubMed  CAS  Google Scholar 

  50. Ostberg JR, et al. Regulatory effects of fever-range whole-body hyperthermia on the LPS-induced acute inflammatory response. J Leukoc Biol. 2000;68(6):815–20.

    PubMed  CAS  Google Scholar 

  51. Jiang Q, et al. Exposure to febrile temperature upregulates expression of pyrogenic cytokines in endotoxin-challenged mice. Am J Physiol. 1999;276(6 Pt 2):R1653–60.

    PubMed  CAS  Google Scholar 

  52. Jiang Q, et al. Febrile-range temperature modifies early systemic tumor necrosis factor alpha expression in mice challenged with bacterial endotoxin. Infect Immun. 1999;67(4):1539–46.

    PubMed  CAS  Google Scholar 

  53. Rosenspire AJ, Kindzelskii AL, Petty HR. Cutting edge: fever-associated temperatures enhance neutrophil responses to lipopolysaccharide: a potential mechanism involving cell metabolism. J Immunol. 2002;169(10):5396–400.

    PubMed  CAS  Google Scholar 

  54. Pritchard MT, Li Z, Repasky EA. Nitric oxide production is regulated by fever-range thermal stimulation of murine macrophages. J Leukoc Biol. 2005;78(3):630–8.

    Article  PubMed  CAS  Google Scholar 

  55. Smith JB, Knowlton RP, Agarwal SS. Human lymphocyte responses are enhanced by culture at 40 degrees C. J Immunol. 1978;121(2):691–4.

    PubMed  CAS  Google Scholar 

  56. Roberts NJ Jr, Steigbigel RT. Effect of in vitro virus infection on response of human monocytes and lymphocytes to mitogen stimulation. J Immunol. 1978;121(3):1052–8.

    PubMed  Google Scholar 

  57. Manzella JP, Roberts NJ Jr. Human macrophage and lymphocyte responses to mitogen stimulation after exposure to influenza virus, ascorbic acid, and hyperthermia. J Immunol. 1979;123(5):1940–4.

    PubMed  CAS  Google Scholar 

  58. Jampel HD, et al. Fever and immunoregulation. III. Hyperthermia augments the primary in vitro humoral immune response. J Exp Med. 1983;157(4):1229–38.

    Article  PubMed  CAS  Google Scholar 

  59. Ciavarra RP, Silvester S, Brody T. Analysis of T-cell subset proliferation at afebrile and febrile temperatures: differential response of Lyt-1+23- lymphocytes to hyperthermia following mitogen and antigen stimulation and its functional consequence on development of cytotoxic lymphocytes. Cell Immunol. 1987;107(2):293–306.

    Article  PubMed  CAS  Google Scholar 

  60. Duff GW. Interleukin-1 and fever. Rheumatology. 1985;XXIV(Suppl 1):12–4.

    Google Scholar 

  61. Oglesbee MJ, et al. Whole body hyperthermia: effects upon canine immune and hemostatic functions. Vet Immunol Immunopathol. 1999;69(2–4):185–99.

    Article  PubMed  CAS  Google Scholar 

  62. Hanson DF. Fever and the immune response. The effects of physiological temperatures on primary murine splenic T-cell responses in vitro. J Immunol. 1993;151(1):436–48.

    PubMed  CAS  Google Scholar 

  63. Cippitelli M, et al. Hyperthermia enhances CD95-ligand gene expression in T lymphocytes. J Immunol. 2005;174(1):223–32.

    PubMed  CAS  Google Scholar 

  64. Yoshioka H, et al. The influence of hyperthermia in vitro on the functions of peritoneal macrophages in mice. Jpn J Surg. 1990;20(1):119–22.

    Article  PubMed  CAS  Google Scholar 

  65. Morimoto RI. Regulation of the heat shock transcriptional response: cross talk between a family of heat shock factors, molecular chaperones, and negative regulators. Genes Dev. 1998;12(24):3788–96.

    Article  PubMed  CAS  Google Scholar 

  66. Tanabe M, et al. Different thresholds in the responses of two heat shock transcription factors, HSF1 and HSF3. J Biol Chem. 1997;272(24):15389–95.

    Article  PubMed  CAS  Google Scholar 

  67. Singh IS, et al. Inhibition of tumor necrosis factor-alpha transcription in macrophages exposed to febrile range temperature. A possible role for heat shock factor-1 as a negative transcriptional regulator. J Biol Chem. 2000;275(13):9841–8.

    Article  PubMed  CAS  Google Scholar 

  68. Nagarsekar A, Hasday JD, Singh IS. CXC chemokines: a new family of heat-shock proteins? Immunol Invest. 2005;34(3):381–98.

    Article  PubMed  CAS  Google Scholar 

  69. Lancaster GI, Febbraio MA. Exosome-dependent trafficking of HSP70: a novel secretory pathway for cellular stress proteins. J Biol Chem. 2005;280(24):23349–55.

    Article  PubMed  CAS  Google Scholar 

  70. Pockley AG. Heat shock proteins as regulators of the immune response. Lancet. 2003;362(9382):469–76.

    Article  PubMed  CAS  Google Scholar 

  71. Ostberg JR, Kaplan KC, Repasky EA. Induction of stress proteins in a panel of mouse tissues by fever-range whole body hyperthermia. Int J Hyperthermia. 2002;18(6):552–62.

    Article  PubMed  CAS  Google Scholar 

  72. Wang XY, Ostberg JR, Repasky EA. Effect of fever-like whole-body hyperthermia on lymphocyte spectrin distribution, protein kinase C activity, and uropod formation. J Immunol. 1999;162(6):3378–87.

    PubMed  CAS  Google Scholar 

  73. Cella M, et al. Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation. J Exp Med. 1996;184:747–52.

    Article  PubMed  CAS  Google Scholar 

  74. Becker T, Hartl FU, Wieland F. CD40, an extracellular receptor for binding and uptake of Hsp70-peptide complexes. J Cell Biol. 2002;158:1277–85.

    Article  PubMed  CAS  Google Scholar 

  75. Dykstra M, et al. Location is everything: lipid rafts and immune cell signaling. Annu Rev Immunol. 2003;21:457–81.

    Article  PubMed  CAS  Google Scholar 

  76. Simons K, Ikonen E. Functional rafts in cell membranes. Nature. 1997;387(6633):569–72.

    Article  PubMed  CAS  Google Scholar 

  77. Brown DA, London E. Functions of lipid rafts in biological membranes. Annu Rev Cell Dev Biol. 1998;14:111–36.

    Article  PubMed  CAS  Google Scholar 

  78. Pralle A, et al. Three-dimensional high-resolution particle tracking for optical tweezers by forward scattered light. Microsc Res Tech. 1999;44(5):378–86.

    Article  PubMed  CAS  Google Scholar 

  79. Chen Q, et al. Central role of IL-6 receptor signal-transducing chain gp130 in activation of L-selectin adhesion by fever-range thermal stress. Immunity. 2004;20(1):59–70.

    Article  PubMed  CAS  Google Scholar 

  80. Ndubuisi MI, et al. Distinct classes of chaperoned IL-6 in human blood: differential immunological and biological availability. J Immunol. 1998;160(1):494–501.

    PubMed  CAS  Google Scholar 

  81. Sehgal PB. Interleukin-6-type cytokines in vivo: regulated bioavailability. Proc Soc Exp Biol Med. 1996;213(3):238–47.

    PubMed  CAS  Google Scholar 

  82. Chen Q, et al. Fever-range thermal stress promotes lymphocyte trafficking across high endothelial venules via an interleukin 6 trans-signaling mechanism. Nat Immunol. 2006;7(12):1299–308.

    Article  PubMed  CAS  Google Scholar 

  83. Payne J, et al. Mild hyperthermia modulates biological activities of interferons. Int J Hyperthermia. 2000;16(6):492–507.

    Article  PubMed  CAS  Google Scholar 

  84. Fleischmann WR Jr, Fleischmann CM, Gindhart TD. Effect of hyperthermia on combination interferon treatment: enhancement of the antiproliferative activity against murine B-16 melanoma. Cancer Res. 1986;46(4 Pt 1):1722–6.

    PubMed  CAS  Google Scholar 

  85. Groveman DS, et al. Augmented antiproliferative effects of interferons at elevated temperatures against human bladder carcinoma cell lines. Cancer Res. 1984;44(12 Pt 1):5517–21.

    PubMed  CAS  Google Scholar 

  86. Williams BRG, Kerr IM. Inhibition of protein synthesis by 2[prime]-5[prime] linked adenine oligonucleotides in intact cells. Nature. 1978;276(5683):88–90.

    Article  PubMed  CAS  Google Scholar 

  87. Chang CC, Wu JM. Modulation of antiviral activity of interferon and 2′,5′-oligoadenylate synthetase gene expression by mild hyperthermia (39.5 degrees C) in cultured human cells. J Biol Chem. 1991;266(7):4605–12.

    PubMed  CAS  Google Scholar 

  88. Orlando A, et al. Radiofrequency thermal ablation vs. percutaneous ethanol injection for small hepatocellular carcinoma in cirrhosis: meta-analysis of randomized controlled trials. Am J Gastroenterol. 2009;104(2):514–24.

    Article  PubMed  Google Scholar 

  89. Timmerman RD, et al. Local surgical, ablative, and radiation treatment of metastases. CA Cancer J Clin. 2009;59(3):145–70.

    Article  PubMed  Google Scholar 

  90. Thrall DE, et al. Changes in tumour oxygenation during fractionated hyperthermia and radiation therapy in spontaneous canine sarcomas. Int J Hyperthermia. 2006;22(5):365–73.

    Article  PubMed  CAS  Google Scholar 

  91. Vujaskovic Z, et al. Temperature-dependent changes in physiologic parameters of spontaneous canine soft tissue sarcomas after combined radiotherapy and hyperthermia treatment. Int J Radiat Oncol Biol Phys. 2000;46(1):179–85.

    Article  PubMed  CAS  Google Scholar 

  92. Song CW, Park H, Griffin RJ. Improvement of tumor oxygenation by mild hyperthermia. Radiat Res. 2001;155(4):515–28.

    Article  PubMed  CAS  Google Scholar 

  93. Dewhirst MW, et al. Re-setting the biological rationale for thermal therapy. Int J Hyperthermia. 2005;21:779–90.

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors thank Dr. Bonnie Hylander and Maegan Capitano for their many helpful comments on this review.

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Correspondence to Elizabeth A. Repasky.

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A. J. Peer and M. J. Grimm contributed equally to this work.

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Peer, A.J., Grimm, M.J., Zynda, E.R. et al. Diverse immune mechanisms may contribute to the survival benefit seen in cancer patients receiving hyperthermia. Immunol Res 46, 137–154 (2010). https://doi.org/10.1007/s12026-009-8115-8

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Keywords

  • Hyperthermia
  • Immune response
  • Dendritic cells
  • NK cells
  • Macrophages
  • T cells
  • Neutrophils
  • Thermal stress