Skip to main content
SpringerLink
Log in

Hyperthermia, the Tumor Microenvironment and Immunity

  • Chapter
  • First Online:
Book cover Tumor Ablation

Part of the book series: The Tumor Microenvironment ((TTME,volume 5))

Abstract

Elevated temperatures produce a wide range of effects in tumor bearing hosts and have been used in cancer therapy. At lower temperatures, in the fever range (FRH) direct tumor cell killing is minimal and cell inactivation is due to profound immune stimulation of a wide range of immune cells under FRH conditions. As temperatures increase above 41 °C, direct cell killing is observed and follows a time and temperature dependent course. Cell death in the “hyperthermia range” (42–47 °C) appears to be due to protein denaturation and is strongly enhanced by properties of the tumor microenvironment such as low glucose and reduced extracellular pH. All cells however possess a powerful resistance mechanism triggered by hyperthermia (thermotolerance), which is mediated by the induction of heat shock proteins (HSPs). HSPs possess molecular chaperone functions, can rapidly repair thermal damage to proteins and lead to thermotolerance. Above 50 °C a different mode of tumor eradication is seen, characterized by cell necrosis and tissue coagulation. The role of the tumor microenvironment in cell killing at these “ablation range” temperatures is not clear. Immune effects of hyperthermia may depend on the mode of cell death that is produced. In broad terms, apoptotic cell death is tolerogenic and absorption of apoptotic cell bodies by immune cells inhibits immunity. Hyperthermia range heating may lead to profound levels of apoptosis and its role in immunity is somewhat ambiguous. However, in the ablation range, cancer cell necrosis dominates and tumor specific immunity is observed, an effect that may play an important role in the outcome of treatment.

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. Hahn GM (1982) Hyperthermia and cancer. Plenum, New York

    Book  Google Scholar 

  2. Harden LM, Du Plessis I, Poole S, Laburn HP (2008) Interleukin (IL)-6 and IL-1 beta act synergistically within the brain to induce sickness behavior and fever in rats. Brain Behav Immun 22:838–849

    Article  PubMed  CAS  Google Scholar 

  3. Nilsberth C et al (2009) The role of interleukin-6 in lipopolysaccharide-induced fever by mechanisms independent of prostaglandin E2. Endocrinology 150:1850–1860

    Article  PubMed  CAS  Google Scholar 

  4. Dickson JA, Calderwood SK (1983) Thermosensitivity of neoplastic tissues. G.K. Hall, Boston

    Google Scholar 

  5. Kraybill WG et al (2002) A phase I study of fever-range whole body hyperthermia (FR-WBH) in patients with advanced solid tumours: correlation with mouse models. Int J Hyperthermia 18:253–266

    Article  PubMed  CAS  Google Scholar 

  6. Webb H, Lubner MG, Hinshaw JL (2011) Thermal ablation. Semin Roentgenol 46:133–141

    Article  PubMed  Google Scholar 

  7. Van Der Zee J et al (2000) Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: a prospective, randomised, multicentre trial. Dutch deep hyperthermia group. Lancet 355:1119–1125

    Article  PubMed  CAS  Google Scholar 

  8. Issels RD (2008) Hyperthermia adds to chemotherapy. Eur J Cancer 44:2546–2554

    Article  PubMed  CAS  Google Scholar 

  9. Folkman J (2006) Angiogenesis. Annu Rev Med 57:1–18

    Article  PubMed  CAS  Google Scholar 

  10. Gullino PM (1966) The internal milieu of tumors. Prog Exp Tumor Res 8:1–25

    PubMed  CAS  Google Scholar 

  11. Dang CV (2010) Rethinking the Warburg effect with Myc micromanaging glutamine metabolism. Cancer Res 70:859–862

    Article  PubMed  CAS  Google Scholar 

  12. Warburg O (1956) On the origin of cancer cells. Science 123:309–314

    Article  PubMed  CAS  Google Scholar 

  13. Pardoll D (2003) Does the immune system see tumors as foreign or self? Annu Rev Immunol 21:807–839

    Article  PubMed  CAS  Google Scholar 

  14. Engelhard VH, Bullock TN, Colella TA, Sheasley SL, Mullins DW (2002) Antigens derived from melanocyte differentiation proteins: self-tolerance, autoimmunity, and use for cancer immunotherapy. Immunol Rev 188:136–146

    Article  PubMed  CAS  Google Scholar 

  15. Srivastava PK, Old LJ (1988) Individually distinct transplantation antigens of chemically induced mouse tumors. Immunol Today 9:78–83

    Article  PubMed  CAS  Google Scholar 

  16. Murshid A, Gong J, Stevenson MA, Calderwood SK (2011) Heat shock proteins and cancer vaccines: developments in the past decade and chaperoning in the decade to come. Expert Rev Vaccines 10:1553–1568

    Article  PubMed  CAS  Google Scholar 

  17. Schatton T, Frank MH (2009) Antitumor immunity and cancer stem cells. Ann N Y Acad Sci 1176:154–169

    Article  PubMed  CAS  Google Scholar 

  18. Ostberg JR, Repasky EA (2000) Use of mild, whole body hyperthermia in cancer therapy. Immunol Invest 29:139–142

    Article  PubMed  CAS  Google Scholar 

  19. Peer AJ, Grimm MJ, Zynda ER, Repasky EA (2010) Diverse immune mechanisms may contribute to the survival benefit seen in cancer patients receiving hyperthermia. Immunol Res 46:137–154

    Article  Google Scholar 

  20. Evans SS et al (2001) Fever-range hyperthermia dynamically regulates lymphocyte delivery to high endothelial venules. Blood 97:2727–2733

    Article  PubMed  CAS  Google Scholar 

  21. Ostberg JR, Dayanc BE, Yuan M, Oflazoglu E, Repasky EA (2007) 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 82:1322–1331

    Article  PubMed  CAS  Google Scholar 

  22. Ostberg JR, Taylor SL, Baumann H, Repasky EA (2000) Regulatory effects of fever-range whole-body hyperthermia on the LPS-induced acute inflammatory response. J Leukoc Biol 68:815–820

    PubMed  CAS  Google Scholar 

  23. Xu Y et al (2007) Fever-range whole body hyperthermia increases the number of perfused tumor blood vessels and therapeutic efficacy of liposomally encapsulated doxorubicin. Int J Hyperthermia 23:513–527

    Article  PubMed  CAS  Google Scholar 

  24. Triantafilou M, Miyake K, Golenbock DT, Triantafilou K (2002) Mediators of innate immune recognition of bacteria concentrate in lipid rafts and facilitate lipopolysaccharide-induced cell activation. J Cell Sci 115:2603–2611

    PubMed  CAS  Google Scholar 

  25. Sen A et al (2011) Mild elevation of body temperature reduces tumor interstitial fluid pressure and hypoxia and enhances efficacy of radiotherapy in murine tumor models. Cancer Res 71:3872–3880

    Article  PubMed  CAS  Google Scholar 

  26. Appenheimer MM et al (2007) Conservation of IL-6 trans-signaling mechanisms controlling L-selectin adhesion by fever-range thermal stress. Eur J Immunol 37:2856–2867

    Article  PubMed  CAS  Google Scholar 

  27. Vardam TD et al (2007) Regulation of a lymphocyte-endothelial-IL-6 trans-signaling axis by fever-range thermal stress: hot spot of immune surveillance. Cytokine 39:84–96

    Article  PubMed  CAS  Google Scholar 

  28. Fisher DT et al (2011) IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells. J Clin Invest 121:3846–3859

    Article  PubMed  CAS  Google Scholar 

  29. Oleson JR et al (1988) Biological and clinical aspects of hyperthermia in cancer therapy. Am J Clin Oncol 11:368–380

    Article  PubMed  CAS  Google Scholar 

  30. Westra A, Dewey WC (1971) Heat shock during the cell cycle of chinese hamster ovary cells in vitro. Int J Radiat Biol 19:467–477

    Article  CAS  Google Scholar 

  31. Gabai VL, Meriin AB, Yaglom JA, Volloch VZ, Sherman MY (1998) Role of Hsp70 in regulation of stress-kinase JNK: implications in apoptosis and aging. FEBS Lett 438 1–4

    Article  PubMed  CAS  Google Scholar 

  32. Gerner EW, Schneider MJ (1975) Induced thermal resistance in HeLa cells. Nature 256:500–502

    Article  PubMed  CAS  Google Scholar 

  33. Li GC, Hahn GM (1981) A proposed operational model for thermotolerance. Cancer Res 40:4501–4508

    Google Scholar 

  34. Craig EA (1985) The stress response: changes in eukaryotic gene expression in response to environmental stress. Science 230:800–801

    Article  PubMed  CAS  Google Scholar 

  35. Subjeck JR, Sciandra JJ, Johnson RJ (1982) Heat shock proteins and thermotolerance; a comparison of induction kinetics. Br J Radiol 55:579–584

    Article  PubMed  CAS  Google Scholar 

  36. Calderwood SK, Dickson JA (1983) pH and tumour response to hyperthermia. Adv Rad Biol 10:135–183

    CAS  Google Scholar 

  37. Song CW, Park H, Griffin, RJ (2001) Improvement of tumor oxygenation by mild hyperthermia. Radiat Res 155:515–528

    Article  PubMed  CAS  Google Scholar 

  38. Jones EL, Zhao MJ, Stevenson MA, Calderwood SK (2004) The 70 kDa heat shock protein is an inhibitor of apoptosis in prostate cancer. Int J Hyperthermia 20:835–849

    Article  PubMed  CAS  Google Scholar 

  39. Tang D 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  PubMed  CAS  Google Scholar 

  40. Mambula SS, Calderwood SK (2006b) Heat shock protein 70 is secreted from tumor cells by a nonclassical pathway involving lysosomal endosomes. J Immunol 177:7849–7857

    CAS  Google Scholar 

  41. Murshid A, Gong J, Calderwood SK (2010) Heat shock protein 90 mediates efficient antigen cross presentation through the scavenger receptor expressed by endothelial cells-I. J Immunol 185:2903–2917

    Article  PubMed  CAS  Google Scholar 

  42. Dickson JA, Calderwood SK (1980) Temperature range and selective sensitivity of tumors to hyperthermia: a critical review. Ann N Y Acad Sci 335:180–205

    Article  PubMed  CAS  Google Scholar 

  43. Zitvogel L et al (2004) Immune response against dying tumor cells. Adv Immunol 84:131–179

    Article  PubMed  CAS  Google Scholar 

  44. Tanaka K et al (2005) Intratumoral injection of immature dendritic cells enhances antitumor effect of hyperthermia using magnetic nanoparticles. Int J Cancer 116:624–633

    Article  PubMed  CAS  Google Scholar 

  45. Guo J et al (2007) Intratumoral injection of dendritic cells in combination with local hyperthermia induces systemic antitumor effect in patients with advanced melanoma. Int J Cancer 120:2418–2425

    Article  PubMed  CAS  Google Scholar 

  46. Mukhopadhaya A et al (2007) Localized hyperthermia combined with intratumoral dendritic cells induces systemic antitumor immunity. Cancer Res 67:7798–7806

    Article  PubMed  CAS  Google Scholar 

  47. Mambula SS, Calderwood SK (2006a) Heat induced release of Hsp70 from prostate carcinoma cells involves both active secretion and passive release from necrotic cells. Int J Hyperthermia 22:575–585

    Article  CAS  Google Scholar 

  48. Skitzki JJ, Repasky EA, Evans SS (2009) Hyperthermia as an immunotherapy strategy for cancer. Curr Opin Investig Drugs 10:550–558

    PubMed  CAS  Google Scholar 

  49. Hinshaw JL, Lee FT Jr (2004) Image-guided ablation of renal cell carcinoma. Magn Reson Imaging Clin N Am 12:429–447

    Article  PubMed  Google Scholar 

  50. Landry J, Marceau N (1978) Rate-limiting events in hyperthermic cell killing. Radiat Res 75:573–585

    Article  PubMed  CAS  Google Scholar 

  51. Mambula SS, Stevenson MA, Ogawa K, Calderwood SK (2007) Mechanisms for Hsp70 secretion: crossing membranes without a leader. Methods 43:168–175

    Article  PubMed  CAS  Google Scholar 

  52. Goldberg SN, Gazelle GS, Mueller PR (2000) Thermal ablation therapy for focal malignancy: a unified approach to underlying principles, techniques, and diagnostic imaging guidance. AJR Am J Roentgenol 174:323–331

    PubMed  CAS  Google Scholar 

  53. Zerbini A et al (2008) Increased immunostimulatory activity conferred to antigen-presenting cells by exposure to antigen extract from hepatocellular carcinoma after radiofrequency thermal ablation. J Immunother 31:271–282

    Article  PubMed  Google Scholar 

  54. Zerbini A et al (2006) Radiofrequency thermal ablation of hepatocellular carcinoma liver nodules can activate and enhance tumor-specific T-cell responses. Cancer Res 66:1139–1146

    Article  PubMed  CAS  Google Scholar 

  55. Kottke T et al (2007) Induction of hsp70-mediated Th17 autoimmunity can be exploited as immunotherapy for metastatic prostate cancer. Cancer Res 67:11970–11979

    Article  PubMed  CAS  Google Scholar 

  56. Chen Z, Shen S, Peng B, Tao J (2009) Intratumoural GM-CSF microspheres and CTLA-4 blockade enhance the antitumour immunity induced by thermal ablation in a subcutaneous murine hepatoma model. Int J Hyperthermia 25:374–382

    Article  PubMed  CAS  Google Scholar 

  57. Waitz R et al (2012) Potent induction of tumor immunity by combining tumor cryoablation with anti-CTLA-4 therapy. Cancer Res 72:430–9

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgement

This work was supported by NIH research grants RO-1CA047407, R01CA119045 and RO-1CA094397.

Author information

Authors and Affiliations

  1. Molecular and Cellular Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Avenue, 02215, Boston, MA, USA

    Stuart K. Calderwood

Authors
  1. Stuart K. Calderwood
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stuart K. Calderwood .

Editor information

Editors and Affiliations

  1. and Immunology, Tel Aviv University, Department of Clinical Microbiology, Tel Aviv, 69978, Israel

    Yona Keisari

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Calderwood, S. (2013). Hyperthermia, the Tumor Microenvironment and Immunity. In: Keisari, Y. (eds) Tumor Ablation. The Tumor Microenvironment, vol 5. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4694-7_2

Download citation

Publish with us

Policies and ethics

Search

Navigation