Advanced
Effects of Regional Hyperthermia with Moderate Temperature on Cancer Treatment
Effects of Regional Hyperthermia with Moderate Temperature on Cancer Treatment
Journal of Life Science. 2016. Sep, 26(9): 1088-1096
Copyright © 2016, Korean Society of Life Science
This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
  • Received : August 23, 2016
  • Accepted : September 21, 2016
  • Published : September 30, 2016
Download
PDF
e-PUB
PubReader
PPT
Export by style
Article
Author
Metrics
Cited by
About the Authors
치덕, 강
kcdshbw@ pusan.ac.kr
선희, 김
kcdshbw@ pusan.ac.kr

Abstract
Despite that moderate hyperthermia can exert various antitumor activities such as direct cytotoxic effects on tumor cells, effects on tumor vasculatures and immunological effects, hyperthermia has been usually combined with radiotherapy or chemotherapy due to its limited efficacy in cancer treatment, showing some positive clinical benefits with generally well-tolerated side effects. Since heat shock responses itself can interfere with the anti-tumor effects of hyperthermia, not all of these studies might have demonstrated positive clinical outcomes in cancer patients. Therefore, the negative anti-tumor effect of hyperthermia should be reduced to enhance the effectiveness of hyperthermia. Although the responses to heat stress of tumor tissues containing vessels, immune cells, connective tissues as well as cancer cells, are very complicated, it is needed to study in the near future if some clinically available drugs, which can modulate heat stress responses, can improve the efficacy of hyperthermia in patients with cancer. In this review, the effect of clinical hyperthermia centered on non-invasive external hyperthermia using radiofrequency at moderate temperature will be discussed, since it is the state-of-the-art technology in the current clinical practice of hyperthermia, and a moderate operational temperature is used to increase the therapeutic effectiveness of conventional therapy without additional toxicity to normal tissues.
Keywords
Introduction
Currently cancer is one of the leading causes of human death worldwide, despite that the three major cancer treatments including surgery, chemotherapy and radiation therapy are being continuously improved. To increase the survival of cancer patients, combination of other therapeutic modalities to current therapies may be required. Many anticancer therapies are under development; for example, immunotherapy, hyperthermia, photodynamic therapy and gene therapy etc. Among these, hyperthermia is one of promising anticancer therapy, since it has been demonstrated that hyperthermia can be used as an adjuvant therapy for the standard cancer treatments such as radiotherapy and chemotherapy [72 , 77] .
The fundamental idea of heat on cancer was originated from the ancient period, during which Hippocrates was aware of the potential of heat to reduce or eliminate tumors [1] , and after that Busch reported complete remission of sarcoma after a high fever due to erysipelas infection in 1868 [28] . This led to development of Coley toxin, named after William B. Coley who had experienced complete responses in 60 out of 210 patients with soft tissue sarcoma for at least 10 years [67] . Although Coley had repeatedly stated that the higher and the longer the fever, the better the effect of the treatment [55] , the major effects of Coley′s Toxin might come primarily from immunological effects as well as thermal effect [28] . After Coley′s death in 1936, clinical interests in the use of his vaccine diminished in preference to the more broadly applicable radiation therapy and chemotherapy [67] .
However, almost at the same time with Coley, in 1898 Westermark observed the pure thermal effects on various gynecological diseases using long-term (48 hr) local (by virtue of intravaginal metal coil heated with circulated water to 42~44℃) and regional (hot tubs) heating, showing the effect of the long-term hyperthermia to treat cancers without damages to healthy normal tissues, and the concept of electromagnetic therapy started from works of Nicola Tesla and Arsen d′Arsonval [55] . Currently, a variety of clinical hyperthermic technologies including thermal conduction using a circulating liquid and exposure by electromagnetic (radiofrequency, microwaves or infrared) or acoustic waves (ultrasound) have been developed and can be broadly categorized into local, regional or whole-body hyperthermia [16 , 23] .
In this review, the effect of clinical hyperthermia centered on non-invasive external hyperthermia using radiofrequency at moderate temperature (41~43℃) will be discussed, since it is the state-of-the-art technology in the current clinical practice of hyperthermia, and an operational range of moderate temperature is used to increase the therapeutic effectiveness of conventional therapy without additional toxicity to normal tissues [18 , 29] .
- Mechanisms of antitumor effects of hyperthermia
The effects of hyperthermia on tumor would be direct or indirect due to its multifactorial effects, and be dependent on temperature and exposure time. Basically, the higher the temperature and exposure time, the higher the direct cytotoxicity of hyperthermia. However, a high temperature and exposure time can injure normal tissues and hamper the indirect effects of hyperthermia on vasculature and immune cells.
- Direct cytotoxic effects of hyperthermia
When exponentially growing cells were exposed to a predefined temperature between 41 and 47℃ in vitro, two phases of direct cytotoxicity were observed in a dose-survival curve, which showed a first linear growth arrest in the beginning of heat exposure, which represents a reversible, non-lethal heat damage, and a second exponential cell death reflecting an irreversible cytotoxicity [17 , 27 , 52] . In this study, temperature of 43℃ seemed to be a critical breakpoint to induce significant cell death, since the induction of cell death at lower temperatures below 42~43℃ is remarkably lower than that at higher temperature above 43℃. This result is related with the reference temperature of 43℃ for calculation of thermal dose, CEM 43℃ T90, the number of cumulative equivalent minutes at 43℃ exceeded by 90% of monitored points within the tumor. A thermal dose (D) derived from exposure time (t) and given temperature (T) can be calculated as D = tR (43-T) with R=0.25 for temperatures ≤43℃, and R=0.5 for temperatures > 43℃ and 10 CEM 43℃ T90 is usually considered as the goal of the hyperthermic therapy [17 , 57] , since it is difficult to uniformly increase the temperature of human tumors above 43℃ in vivo without damages to normal tissues using the currently available hyperthermia devices.
An increased temperature results in both unbalanced metabolism and changes in cellular structures such as membranes and macromolecules [27 , 41] . The molecular effects of hyperthermia are dysfunction of cell membrane including changes in fluidity of cell membrane and impairment of membrane transport, protein denaturation, impairment of DNA/RNA/protein synthesis, inhibition of DNA repair enzymes, and alterations of intracellular metabolism, gene expression and signal transduction [41 , 54] . These cellular responses to hyperthermia are thought to be rerated with the cytotoxic effects of hyperthermia, and protein denaturation seemed to be the rate limiting step for hyperthermic cell death and for any other thermal effect with a high activation energy, since the thermal energy dose required for cellular protein denaturation is closely correlated to that required to induce exponential cell death [27 , 41] .
Although many preclinical and clinical studies have shown that cancer cells are more sensitive to moderate hyperthermia (42~45℃) than normal cells, it is unknown why cancer cells exhibit this distinctive susceptibility to moderate hyperthermia at molecular and cellular levels. Recently, a genomics approach involving microarray, bioinformatics, and network analysis of the global transcription changes revealed that hyperthermia specifically disrupts the expression of key mitotic regulators including KIF11, CDK6, STAG2, NEK2, CHUK, KPNA4, CENPF , and NCAPG , and G2/M phase progression in the breast cancer cells, compared with mammary epithelial cells, suggesting that the selective disadvantage of breast cancer cell lines in response to hyperthermia may be due to an inability to correctly regulate their core biological processes and mitotic cell cycle machinery [2] .
- Effects of hyperthermia on tumor vasculature
Besides direct cytotoxic effect of hyperthermia, high temperature has indirect effects on tumor growth through change of intratumoral blood flow in vivo . The tumor vasculature is very different from that of normal tissues, since angiogenesis in tumor is unable to keep pace with the rapid proliferation of neoplastic cells. Due to structurally chaotic vasculatures in tumors, tumor vessels have numerous functional abnormalities, such as unstable speed and direction of blood flow, high vascular resistance, and increased vascular fragility, and consequently abnormal areas develop within the tumor that are characterized by deprivation of glucose and energy, high lactate levels, extracellular acidosis, and oxygen deficiency [64] .
The change of intratumoral blood flow caused by heating is dependent on the temperature and duration of hyperthermia. It has been demonstrated that in FSaII murine fibrosarcoma model the pO 2 increased progressively during 1 hr heating at 41.5℃, and heating at higher temperatures failed to increase or even reduced the pO 2 , and in R3230 rat mammary adenocarcinoma model the highest level of pO 2 was achieved by heating at 42.5℃ for 30 min [33] , suggesting that modest temperature hyperthermia may be an efficient and useful means to improve the effect of radiotherapy and chemotherapy through an increased oxygenation and drug delivery in human tumors. However, at higher temperature and longer duration, tumor tissue could be overheated. In normal tissue blood vessels dilate in response to high temperature, resulting in an increase in blood flow through the heated region and a consequent dissipation of heat. In contrast, aberrant vessels in tumor tissues are not able to dilate, some of them collapse, and consequently intratumoural temperature will increase due to loss of heat dissipation. [11] . In addition, delivery of oxygen and nutrient to heated tumor is impaired, and intratumoral lactic acidosis is induced [27] . Finally, the heated tumor cells will undergo necrotic or apoptotic death.
- Immunological effects of hyperthermia
In addition to local effects on tumor tissues of hyperthermia described above, hyperthermia can work systemically through stimulation of tumor-specific immunity, and consequently can be regarded as in situ anti-tumor vaccine. The heat shock response, a major response to stress conditions in the cytosol [47] , is mediated by heat shock factor 1 (HSF1), a transcription factor [80] . In unstressed cells HSF1 is sequestered as a monomer in the cytoplasm by Hsp90 and co-chaperones. When cells are heated, accumulation of denatured and misfolded cellular proteins results in depletion of chaperones available for the assembly of HSF1 inhibitory complex, and upon its release from the Hsp90 complex an active HSF1 trimer is formed and subsequently enhances the transcription of the so-called heat shock genes [61 , 68 , 73] .
The heat shock proteins (Hsps) including Hsp70, Hsp90 and gp96, an endoplasmic reticulum paralog of Hsp90, can form complexes with a broad spectrum of cellular proteins and peptides due to their chaperone functions. In addition to their intracellular chaperoning functions, extracellular complexes of Hsps play key roles in eliciting antitumor immune responses. Vaccination with these complexes elicits specific immunity against the tumor from which the Hsps were purified, albeit the immunogenicity of Hsp90 was approximately 10% of that of gp96 or Hsp70 [6 , 26 , 32 , 63 , 66 , 70] . It has been known that Hsp70 either alone, bound to exosomes or in combination with tumor-derived peptides, which can be released from heat-stressed tumor cells, is able to stimulate the maturation and antigen-presenting function of dendritic cells (DCs), activate NK cells and T cell, and induce the release of pro- and anti-inflammatory cytokines from macrophages [20 , 63 , 65 , 69] . In addition, following non-lethal heat stress Hsp72 can be expressed on the cell surface of heat-stressed tumor cells including sarcoma and leukemic cells, and subsequently these cells can be recognized and killed by NK effector cells through a heat-inducible immunogenic determinant associated with Hsp72 [49 , 50 , 48] . The effects of moderate temperature may be similar with those of radiofrequency ablation in the transitional zone in which various inflammatory cells such as neutrophils, macrophages, DCs, NK cells, as well as B and T cells are infiltrated by stimulation with various immunogenic intracellular substrates including RNA, DNA, Hsps, uric acid and high mobility group protein B1 (HMGB1) released from the sublethally heat-damaged cells [12] . Recently, spontaneous regressions of multiple distant metastatic lesions have been reported after percutaneous radiofrequency ablation of primary or recurrent renal cell carcinoma, suggesting a possible mediation of systemic antitumor immune response induced by local hyperthermia [36 , 56]
In addition to Hsps, some of NKG2D (natural-killer group 2, member D) ligands with heat shock element in their promoter that bind HSF1, can be induced by heat shock [22 , 37] . NKG2D ligands can be recognized by NKG2D, one of the most important activating receptors expressed on the vast majority of NK and NKT cells, CD8+ T cells and γδ T cells, and on certain subsets of human CD4+ T cells [42 , 53] . Therefore, hyperthermia may increase tumor cell recognition by immune cells with NKG2D receptor via induction of NKG2D ligands on heat-treated tumor cells.
- Self-interference of hyperthermia with its antitumor effects
Despite of various antitumor effects of hyperthermia, the clinical results obtained by hyperthermia alone have not been satisfactory. Due to the limited efficacy of hyperthermia in cancer treatment, hyperthermia has been usually combined with radiotherapy or chemotherapy, showing positive clinical benefits with generally well-tolerated side effects in randomized trials with a variety of malignancies, possibly through the effects of hyperthermia described above [13 , 16 , 43] . Although many of these studies have demonstrated positive clinical outcomes when hyperthermia is combined with other treatments, but not all, possibly due to some technical problems, such as the inability of real-time non-invasive monitoring of tissue temperature, and difficulties to focus heat to the target tumors. In addition to these technical problems, heat shock responses itself may interfere with the anti-tumor effects of hyperthermia, playing as double-edged swords.
Although Hsps can be induced as a major heat shock response and stimulate tumor-specific immunity, the induced Hsp27, Hsp70, and Hsp90 can inhibit both caspase-dependent and -independent apoptotic pathways at various levels, providing protection of cells from apoptosis-inducing stimuli such as radiotherapy, chemotherapy and second heat shock [7 , 8 , 31 , 35 , 40] . Therefore, inhibition of Hsps function may be required to improve efficacy of hyperthermia.
Tumor-cell derived exosomes are considered as an efficient anti-tumor vaccine, since they are a source of tumor antigens [3 , 76] . Exosomes harvested from various heated human tumor cells carry enriched tumor antigens and chemokines, such as CCL2, CCL3, CCL4, CCL5 and CCL20, and act as an efficient anti-tumor vaccine [10 , 15 , 79] . However, tumor-derived exosomes have also immunosuppressive properties [44] . It has been shown that thermal and oxidative stresses enhance the release of immunosuppressive exosomes bearing NKG2D ligands in both Jurkat leukemia T cells and Raji lymphoma B cells [25] . Exosomes can express differentially and constitutively NKG2D ligands from both MICA/B (MHC class I-related chain A/B) and ULBP (UL16-binding proteins) families on their surface. Consequently, the NKG2D ligand-expressing exosomes serve as decoys with a powerful ability to downregulate the NKG2D receptor and impair the cytotoxic function of NK and NKT cells, CD8+ T cells, γδ T cells and CD4+ T cells [39 , 46] . Some tumor cells release proapoptotic exosomes bearing death ligands such as Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), inducing apoptosis of activated T cells [4 , 30] . Exosomes can also enhance the immunosuppressive functions of myeloid-derived suppressor cells (MDSCs) and regulatory T cells through a TGF-β-dependent mechanism [14 , 69 , 71] . Recently, it has been shown that an interaction between tumor-derived exosomes-associated Hsp72 and MDSCs mediates the immunosuppressive activity of the MDSCs via activation of STAT3 in a TLR2/MyD88-dependent manner through autocrine production of IL-6 [9] .
Meanwhile, hyperthermia can suppress the function of immune cells directly. Several studies have demonstrated impairments of cytotoxic function in lymphocytes, especially NK cells, after heat treatment. Cytotoxic activities of NK cells and lymphokine-activated killer cells could be enhanced at febrile range (≤40℃), but were significantly reduced at 42℃ for 1 hr [62 , 78] . When the effector and target cells were exposed simultaneously to hyperthermia (42℃ for 1 hr) during the cytotoxicity assay, the lytic activity of NK and IL-2-activated NK cells was remarkably reduced [21] . The impairment of human NK cell cytotoxicity may result from downregulation of perforin, and is transient in vitro and in vivo [20 , 24] . Therefore, due to these non-beneficial effects of hyperthermia on immune cells, temperature about 42℃ may be appropriate for locoregional hyperthermia.
- Tuning of hyperthermia
As described above, various mechanisms which are activated by hyperthermia are involved in interference of the antitumor effects of hyperthermia. To enhance the effectiveness of hyperthermia, the negative anti-tumor effect of hyperthermia should be reduced. Basically, it is not possible to remove only the negative side of hyperthermia in the treatment of cancer, while keeping the positive effect of hyperthermia. Nevertheless, we need to find out the best way to enhance the antitumor effects of hyperthermia.
The cytoprotective functions of Hsps are essential for survival of cancer cells. Therefore, inhibition of Hsps may be able to improve direct cytotoxic effects of hyperthermia. Hsp90 has regarded as a major pharmaceutical target in cancer therapy, due to its function of molecular chaperone, which is known to bind and stabilize numerous oncoproteins with activity in the cell cycle, signal transduction and transcription [5 , 74] . However, inhibition of Hsp90 results in disruption of complexes of Hsp90 with HSF1, thereby causing HSF1-mediated induction of cytoprotective Hsp70 and Hsp27, which contribute to resistance to Hsp90 inhibitors [51] . Therefore, inhibition of Hsps or HSF1 would be required to prevent the Hsp90 inhibitor-mediated rebound induction of cytoprotective Hsps. In addition, Hsp70 neutralization induces tumor regression in animal models of colon cancer and melanoma by inducing anti-tumor immune responses [60] , and this antitumor immunity might be explained by the prevention of the interaction between tumor-derived exosomes-associated Hsp72 and MDSCs [9] . Currently, many inhibitors of Hsps are under development and clinical trials [34] . HSF1 may be also a good target to enhance the efficacy of hyperthermia, since HSF-1 is a key regulator of Hsp90 and Hsp70 expression. Several small molecules such as quercetin, KNK437 and triptolide are identified as inhibitors of HSF1 and entered into clinical development [75] . However, development of specific inhibitors of Hsps and HSF1 has been delayed, and currently are not available commercially. Recently, it has been reported that ibuprofen, a nonsteroidal anti-inflammatory drug, significantly suppresses Hsp70 expression by depleting HSF1 in lung adenocarcinoma-derived A549 cells [19] . In this study, ibuprofen enhances the anticancer activity of cisplatin, possibly through suppression of Hsp70 expression. Therefore, it is needed to study if ibuprofen can improve the efficacy of hyperthermia in cancer patients.
Like Hsps, tumor-derived exosomes also have pro-tumorigenic as well as anti-tumorigenic properties. Therefore, depletion of tumor-derived exosomes may give some benefits to survival of cancer patients. It has been demonstrated that dimethyl amiloride, an anti-hypertensive drug that also inhibits exosome formation [58] , can decrease exosome production and consequently reduces suppressor functions of MDSCs from cancer patients, restoring the efficacy of low dose cyclophosphamide, which is related to its capability of inducing a T cell-dependent immune response through elimination of regulatory T cells rather than to its cytotoxic effect on tumor cells [9] . Another promising strategy to remove exosomes from the entire circulatory system involves extracorporeal hemofiltration system [44] . If the exosome from heat-stressed cancer cells can be decreased, the efficacy of hyperthermia would be increased through an enhanced anti-tumor immunity.
Although a variety of anti-tumor vaccines is currently being evaluated, only one therapeutic cancer vaccine (sipuleucel-T) has been approved by the US Food and Drug Administration for the treatment of cancer, possibly due to profound influence of immunosuppressive microenvironment of tumor, limiting the effectiveness of anti-tumor vaccines [59] . The efficacy of hyperthermia as an in situ anti-tumor vaccine may also be limited by same causes. Currently, numerous strategies including the combination of vaccines with immune checkpoint inhibitors, certain chemotherapeutics, small-molecule targeted therapies, and radiation are being evaluated to counteract the immunosuppressive microenvironment of tumor [59] . Among those the immune checkpoint inhibitors including anti-CTLA4 and anti-PD1 monoclonal antibodies are at the center of current development of combination with vaccines [45 , 59] , and many cytotoxic anticancer drugs given in lower-than therapeutic doses can not only eliminate tumor cells but also block the immunosuppressive activities in tumor microenvironments and consequently favor the development of anticancer immune responses [38] . Therefore, clinically available cytotoxic drugs in low doses and the immune checkpoint inhibitors can be considered for their early combination with hyperthermia to enhance its efficacy.
Although the responses to heat stress of tumor tissues containing vessels, immune cells as well as cancer cells, are very complicated, and it is hard to expect the consequences of treatment with modulators of heat shock responses, it is needed to study in the near future if some clinically available drugs such as ibuprofen, amiloride, immune checkpoint inhibitors, and low dose of some cytotoxic anticancer drugs, which can modulate heat stress responses, can improve the efficacy of hyperthermia in cancer patients ( Fig. 1 ).
PPT Slide
Lager Image
Anti-tumorigenic and pro-tumorigenic effects of hyperthermia and modulation of heat shock responses with clinically available drugs (ellipses) to improve the anti-tumorigenic effects of hypethermia.
Acknowledgements
This study was supported by a 2-Year Research Grant from Pusan National University.
References
Ahmed K. , Zaidi S. F. 2013 Treating cancer with heat: hyperthermia as promising strategy to enhance apoptosis J. Pak. Med. Assoc. 63 504 - 508
Amaya C. , Kurisetty V. , Stiles J. , Nyakeriga A. M. , Arumugam A. , Lakshmanaswamy R. , Botez C. E. , Mitchell D. C. , Bryan B. A. 2014 A genomics approach to identify susceptibilities of breast cancer cells to "fever-range" hyperthermia BMC Cancer 14 81 -    DOI : 10.1186/1471-2407-14-81
Andre F. , Schartz N. E. , Movassagh M. , Flament C. , Pautier P. , Morice P. , Pomel C. , Lhomme C. , Escudier B. , Le Chevalier T. , Tursz T. , Amigorena S. , Raposo G. , Angevin E. , Zitvogel L. 2002 Malignant effusions and immunogenic tumour-derived exosomes Lancet 360 295 - 305    DOI : 10.1016/S0140-6736(02)09552-1
Andreola G. , Rivoltini L. , Castelli C. , Huber V. , Perego P. , Deho P. , Squarcina P. , Accornero P. , Lozupone F. , Lugini L. , Stringaro A. , Molinari A. , Arancia G. , Gentile M. , Parmiani G. , Fais S. 2002 Induction of lymphocyte apoptosis by tumor cell secretion of FasL-bearing microvesicles J. Exp. Med. 195 1303 - 1316    DOI : 10.1084/jem.20011624
Banerji U. 2009 Heat shock protein 90 as a drug target: some like it hot Clin. Cancer Res. 15 9 - 14    DOI : 10.1158/1078-0432.CCR-08-0132
Binder R. J. , Srivastava P. K. 2005 Peptides chaperoned by heat-shock proteins are a necessary and sufficient source of antigen in the cross-priming of CD8+ T cells Nat. Immunol. 6 593 - 599
Calderwood S. K. , Khaleque M. A. , Sawyer D. B. , Ciocca D. R. 2006 Heat shock proteins in cancer: chaperones of tumorigenesis Trends Biochem. Sci. 31 164 - 172    DOI : 10.1016/j.tibs.2006.01.006
Calderwood S. K. , Theriault J. R. , Gong J. 2005 How is the immune response affected by hyperthermia and heat shock proteins? Int. J. Hyperthermia 21 713 - 716    DOI : 10.1080/02656730500340794
Chalmin F. , Ladoire S. , Mignot G. , Vincent J. , Bruchard M. , Remy-Martin J. P. , Boireau W. , Rouleau A. , Simon B. , Lanneau D. , De Thonel A. , Multhoff G. , Hamman A. , Martin F. , Chauffert B. , Solary E. , Zitvogel L. , Garrido C. , Ryffel B. , Borg C. , Apetoh L. , Rebe C. , Ghiringhelli F. 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
Chen T. , Guo J. , Yang M. , Zhu X. , Cao X. 2011 Chemokine-containing exosomes are released from heatstressed tumor cells via lipid raft-dependent pathway and act as efficient tumor vaccine J Immunol. 186 2219 - 2228    DOI : 10.4049/jimmunol.1002991
Chicheł A. , Skowronek J. , Kubaszewska M. , Kanikowski M. 2007 Hyperthermia – description of a method and a review of clinical applications Rep. Pract. Oncol. Radiother. 12 267 - 275    DOI : 10.1016/S1507-1367(10)60065-X
Chu K. F. , Dupuy D. E. 2014 Thermal ablation of tumours: biological mechanisms and advances in therapy Nat. Rev. Cancer 14 199 - 208    DOI : 10.1038/nrc3672
Cihoric N. , Tsikkinis A. , van Rhoon G. , Crezee H. , Aebersold D. M. , Bodis S. , Beck M. , Nadobny J. , Budach V. , Wust P. , Ghadjar P. 2015 Hyperthermia-related clinical trials on cancer treatment within the ClinicalTrials. gov registry Int. J. Hyperthermia 31 609 - 614    DOI : 10.3109/02656736.2015.1040471
Clayton A. , Mitchell J. P. , Court J. , Mason M. D. , Tabi Z. 2007 Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2 Cancer Res. 67 7458 - 7466    DOI : 10.1158/0008-5472.CAN-06-3456
Dai S. , Wan T. , Wang B. , Zhou X. , Xiu F. , Chen T. , Wu Y. , Cao X. 2005 More efficient induction of HLA-A* 0201-restricted and carcinoembryonic antigen (CEA)-specific CTL response by immunization with exosomes prepared from heat-stressed CEA-positive tumor cells Clin. Cancer Res. 11 7554 - 7563    DOI : 10.1158/1078-0432.CCR-05-0810
Datta N. R. , Ordonez S. G. , Gaipl U. S. , Paulides M. M. , Crezee H. , Gellermann J. , Marder D. , Puric E. , Bodis S. 2015 Local hyperthermia combined with radiotherapy and-/or chemotherapy: recent advances and promises for the future Cancer Treat. Rev. 41 742 - 753    DOI : 10.1016/j.ctrv.2015.05.009
Dewhirst M. W. , Viglianti B. L. , Lora-Michiels M. , Hanson M. , Hoopes P. J. 2003 Basic principles of thermal dosimetry and thermal thresholds for tissue damage from hyperthermia Int. J. Hyperthermia 19 267 - 294    DOI : 10.1080/0265673031000119006
Dickson J. A. , Calderwood S. K. 1980 Temperature range and selective sensitivity of tumors to hyperthermia: a critical review Ann. N. Y. Acad. Sci. 335 180 - 205    DOI : 10.1111/j.1749-6632.1980.tb50749.x
Endo H. , Yano M. , Okumura Y. , Kido H. 2014 Ibuprofen enhances the anticancer activity of cisplatin in lung cancer cells by inhibiting the heat shock protein 70 Cell Death Dis. 5 e1027 -    DOI : 10.1038/cddis.2013.550
Frey B. , Weiss E. M. , Rubner Y. , Wunderlich R. , Ott O. J. , Sauer R. , Fietkau R. , Gaipl U. S. 2012 Old and new facts about hyperthermia-induced modulations of the immune system Int. J. Hyperthermia 28 528 - 542    DOI : 10.3109/02656736.2012.677933
Fuggetta M. P. , Alvino E. , Tricarico M. , D′Atri S. , Pepponi R. , Prete S. P. , Bonmassar E. 2000 In vitro effect of hyperthermia on natural cell-mediated cytotoxicity Anticancer Res. 20 1667 - 1672
Groh V. , Bahram S. , Bauer S. , Herman A. , Beauchamp M. , Spies T. 1996 Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium Proc. Natl. Acad. Sci. USA 93 12445 - 12450    DOI : 10.1073/pnas.93.22.12445
Habash R. W. , Bansal R. , Krewski D. , Alhafid H. T. 2006 Thermal therapy, part 2: hyperthermia techniques Crit. Rev. Biomed. Eng. 34 491 - 542    DOI : 10.1615/CritRevBiomedEng.v34.i6.30
Harada H. , Murakami T. , Tea S. S. , Takeuchi A. , Koga T. , Okada S. , Suico M. A. , Shuto T. , Kai H. 2007 Heat shock suppresses human NK cell cytotoxicity via regulation of perforin Int. J. Hyperthermia 23 657 - 665    DOI : 10.1080/02656730701822087
Hedlund M. , Nagaeva O. , Kargl D. , Baranov V. , Mincheva-Nilsson L. 2011 Thermal- and oxidative stress causes enhanced release of NKG2D ligand-bearing immunosuppressive exosomes in leukemia/lymphoma T and B cells PLoS One 6 e16899 -    DOI : 10.1371/journal.pone.0016899
Heike M. , Noll B. , Meyer zum Buschenfelde K. H. 1996 Heat shock protein-peptide complexes for use in vaccines J. Leukoc. Biol. 60 153 - 158
Hildebrandt B. , Wust P. , Ahlers O. , Dieing A. , Sreenivasa G. , Kerner T. , Felix R. , Riess H. 2002 The cellular and molecular basis of hyperthermia Crit. Rev. Oncol. Hematol. 43 33 - 56    DOI : 10.1016/S1040-8428(01)00179-2
Hobohm U. 2001 Fever and cancer in perspective Cancer Immunol. Immunother. 50 391 - 396
Horsman M. R. , Overgaard J. 2007 Hyperthermia: a potent enhancer of radiotherapy Clin. Oncol. (R. Coll. Radiol.) 19 418 - 426    DOI : 10.1016/j.clon.2007.03.015
Huber V. , Fais S. , Iero M. , Lugini L. , Canese P. , Squarcina P. , Zaccheddu A. , Colone M. , Arancia G. , Gentile M. , Seregni E. , Valenti R. , Ballabio G. , Belli F. , Leo E. , Parmiani G. , Rivoltini L. 2005 Human colorectal cancer cells induce T-cell death through release of proapoptotic microvesicles: role in immune escape Gastroenterology 128 1796 - 1804    DOI : 10.1053/j.gastro.2005.03.045
Ischia J. , So A. I. 2013 The role of heat shock proteins in bladder cancer Nat. Rev. Urol. 10 386 - 395    DOI : 10.1038/nrurol.2013.108
Ishii T. , Udono H. , Yamano T. , Ohta H. , Uenaka A. , Ono T. , Hizuta A. , Tanaka N. , Srivastava P. K. , Nakayama E. 1999 Isolation of MHC class I-restricted tumor antigen peptide and its precursors associated with heat shock proteins hsp70, hsp90, and gp96 J. Immunol. 162 1303 - 1309
Iwata K. , Shakil A. , Hur W. J. , Makepeace C. M. , Griffin R. J. , Song C. W. 1996 Tumour pO2 can be increased markedly by mild hyperthermia Br. J. Cancer Suppl. 27 S217 - 221
Jego G. , Hazoume A. , Seigneuric R. , Garrido C. 2013 Targeting heat shock proteins in cancer Cancer Lett. 332 275 - 285    DOI : 10.1016/j.canlet.2010.10.014
Kennedy D. , Jager R. , Mosser D. D. , Samali A. 2014 Regulation of apoptosis by heat shock proteins IUBMB Life 66 327 - 338    DOI : 10.1002/iub.1274
Kim H. , Park B. K. , Kim C. K. 2008 Spontaneous regression of pulmonary and adrenal metastases following percutaneous radiofrequency ablation of a recurrent renal cell carcinoma Kor. J. Radiol. 9 470 - 472    DOI : 10.3348/kjr.2008.9.5.470
Kim J. Y. , Son Y. O. , Park S. W. , Bae J. H. , Chung J. S. , Kim H. H. , Chung B. S. , Kim S. H. , Kang C. D. 2006 Increase of NKG2D ligands and sensitivity to NK cell-mediated cytotoxicity of tumor cells by heat shock and ionizing radiation Exp. Mol. Med. 38 474 - 484    DOI : 10.1038/emm.2006.56
Kim S. J. , Ha G. H. , Kim S. H. , Kang C. D. 2014 Combination of cancer immunotherapy with clinically available drugs that can block immunosuppressive cells Immunol. Invest. 43 517 - 534    DOI : 10.3109/08820139.2013.857352
Labani-Motlagh A. , Israelsson P. , Ottander U. , Lundin E. , Nagaev I. , Nagaeva O. , Dehlin E. , Baranov V. , Mincheva-Nilsson L. 2016 Differential expression of ligands for NKG2D and DNAM-1 receptors by epithelial ovarian cancer-derived exosomes and its influence on NK cell cytotoxicity Tumour Biol. 37 5455 - 5466    DOI : 10.1007/s13277-015-4313-2
Lanneau D. , Brunet M. , Frisan E. , Solary E. , Fontenay M. , Garrido C. 2008 Heat shock proteins: essential proteins for apoptosis regulation J. Cell Mol. Med. 12 743 - 761    DOI : 10.1111/j.1582-4934.2008.00273.x
Lepock J. R. 2003 Cellular effects of hyperthermia: relevance to the minimum dose for thermal damage Int. J. Hyperthermia 19 252 - 266    DOI : 10.1080/0265673031000065042
Lopez-Soto A. , Huergo-Zapico L. , Acebes-Huerta A. , Villa-Alvarez M. , Gonzalez S. 2015 NKG2D signaling in cancer immunosurveillance Int. J. Cancer 136 1741 - 1750    DOI : 10.1002/ijc.28775
Mallory M. , Gogineni E. , Jones G. C. , Greer L. , Simone C. B. 2016 Therapeutic hyperthermia: The old, the new, and the upcoming Crit. Rev. Oncol. Hematol. 97 56 - 64    DOI : 10.1016/j.critrevonc.2015.08.003
Marleau A. M. , Chen C. S. , Joyce J. A. , Tullis R. H. 2012 Exosome removal as a therapeutic adjuvant in cancer J. Transl. Med. 10 134 -    DOI : 10.1186/1479-5876-10-134
Melero I. , Berman D. M. , Aznar M. A. , Korman A. J. , Perez Gracia J. L. , Haanen J. 2015 Evolving synergistic combinations of targeted immunotherapies to combat cancer Nat. Rev. Cancer 15 457 - 472    DOI : 10.1038/nrc3973
Mincheva-Nilsson L. , Baranov V. 2014 Cancer exosomes and NKG2D receptor-ligand interactions: impairing NKG2D-mediated cytotoxicity and anti-tumour immune surveillance Semin. Cancer Biol. 28 24 - 30    DOI : 10.1016/j.semcancer.2014.02.010
Morimoto R. I. 1998 Regulation of the heat shock transcriptional response: cross talk between a family of heat shock factors, molecular chaperones, and negative regulators Genes Dev. 12 3788 - 3796    DOI : 10.1101/gad.12.24.3788
Multhoff G. 1997 Heat shock protein 72 (HSP72), a hyperthermia-inducible immunogenic determinant on leukemic K562 and Ewing's sarcoma cells Int. J. Hyperthermia 13 39 - 48    DOI : 10.3109/02656739709056428
Multhoff G. , Botzler C. , Wiesnet M. , Eissner G. , Issels R. 1995 CD3- large granular lymphocytes recognize a heat-inducible immunogenic determinant associated with the 72-kD heat shock protein on human sarcoma cells Blood 86 1374 - 1382
Multhoff G. , Botzler C. , Wiesnet M. , Muller E. , Meier T. , Wilmanns W. , Issels R. D. 1995 A stress-inducible 72-kDa heat-shock protein (HSP72) is expressed on the surface of human tumor cells, but not on normal cells Int. J. Cancer 61 272 - 279    DOI : 10.1002/ijc.2910610222
Piper P. W. , Millson S. H. 2011 Mechanisms of resistance to Hsp90 inhibitor drugs: a complex mosaic emerges Pharmaceuticals 1400 - 1422
Rampersaud E. N. , Vujaskovic Z. , Inman B. A. 2010 Hyperthermia as a treatment for bladder cancer Oncology (Williston Park) 24 1149 - 1155
Raulet D. H. , Gasser S. , Gowen B. G. , Deng W. , Jung H. 2013 Regulation of ligands for the NKG2D activating receptor Annu. Rev. Immunol. 31 413 - 441    DOI : 10.1146/annurev-immunol-032712-095951
Richter K. , Haslbeck M. , Buchner J. 2010 The heat shock response: life on the verge of death Mol. Cell 40 253 - 266    DOI : 10.1016/j.molcel.2010.10.006
Roussakow S. 2013 The History of Hyperthermia Rise and Decline Conference Papers in Medicine 2013
Sanchez-Ortiz R. F. , Tannir N. , Ahrar K. , Wood C. G. 2003 Spontaneous regression of pulmonary metastases from renal cell carcinoma after radio frequency ablation of primary tumor: an in situ tumor vaccine? J. Urol. 170 178 - 179    DOI : 10.1097/01.ju.0000070823.38336.7b
Sapareto S. A. , Dewey W. C. 1984 Thermal dose determination in cancer therapy Int. J. Radiat. Oncol. Biol. Phys. 10 787 - 800    DOI : 10.1016/0360-3016(84)90379-1
Savina A. , Furlan M. , Vidal M. , Colombo M. I. 2003 Exosome release is regulated by a calcium-dependent mechanism in K562 cells J. Biol. Chem. 278 20083 - 20090    DOI : 10.1074/jbc.M301642200
Schlom J. 2012 Therapeutic cancer vaccines: current status and moving forward J. Natl. Cancer Inst. 104 599 - 613    DOI : 10.1093/jnci/djs033
Schmitt E. , Maingret L. , Puig P. E. , Rerole A. L. , Ghiringhelli F. , Hammann A. , Solary E. , Kroemer G. , Garrido C. 2006 Heat shock protein 70 neutralization exerts potent antitumor effects in animal models of colon cancer and melanoma Cancer Res. 66 4191 - 4197    DOI : 10.1158/0008-5472.CAN-05-3778
Shamovsky I. , Nudler E. 2008 New insights into the mechanism of heat shock response activation Cell Mol. Life Sci. 65 855 - 861    DOI : 10.1007/s00018-008-7458-y
Shen R. N. , Lu L. , Young P. , Shidnia H. , Hornback N. B. , Broxmeyer H. E. 1994 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. 29 821 - 826    DOI : 10.1016/0360-3016(94)90571-1
Shevtsov M. , Multhoff G. 2016 Heat shock proteinpeptide and HSP-based immunotherapies for the treatment of cancer Front. Immunol. 7 171 -
Siemann D. W. , Horsman M. R. 2015 Modulation of the tumor vasculature and oxygenation to improve therapy Pharmacol. Ther. 153 107 - 124    DOI : 10.1016/j.pharmthera.2015.06.006
Srivastava P. K. , Amato R. J. 2001 Heat shock proteins: the ′Swiss Army Knife′ vaccines against cancers and infectious agents Vaccine 19 2590 - 2597    DOI : 10.1016/S0264-410X(00)00492-8
Srivastava P. K. , Udono H. 1994 Heat shock protein-peptide complexes in cancer immunotherapy Curr. Opin. Immunol. 6 728 - 732    DOI : 10.1016/0952-7915(94)90076-0
Starnes C. O. 1992 Coley's toxins in perspective Nature 357 11 - 12    DOI : 10.1038/357011a0
Tonkiss J. , Calderwood S. K. 2005 Regulation of heat shock gene transcription in neuronal cells Int J Hyperthermia 21 433 - 444    DOI : 10.1080/02656730500165514
Toraya-Brown S. , Fiering S. 2014 Local tumour hyperthermia as immunotherapy for metastatic cancer Int. J. Hyperthermia 30 531 - 539    DOI : 10.3109/02656736.2014.968640
Udono H. , Srivastava P. K. 1994 Comparison of tumor-specific immunogenicities of stress-induced proteins gp96, hsp90, and hsp70 J. Immunol. 152 5398 - 5403
Valenti R. , Huber V. , Filipazzi P. , Pilla L. , Sovena G. , Villa A. , Corbelli A. , Fais S. , Parmiani G. , d Rivoltini L. 2006 Human tumor-released microvesicles promote the differentiation of myeloid cells with transforming growth factor-beta-mediated suppressive activity on T lymphocytes Cancer Res. 66 9290 - 9298    DOI : 10.1158/0008-5472.CAN-06-1819
van der Zee J. 2002 Heating the patient: a promising approach? Ann. Oncol. 13 1173 - 1184    DOI : 10.1093/annonc/mdf280
Voellmy R. 1994 Transduction of the stress signal and mechanisms of transcriptional regulation of heat shock/stress protein gene expression in higher eukaryotes Crit. Rev. Eukaryot. Gene Expr. 4 357 - 401
Whitesell L. , Lin N. U. 2012 HSP90 as a platform for the assembly of more effective cancer chemotherapy Biochim. Biophys. Acta 1823 756 - 766    DOI : 10.1016/j.bbamcr.2011.12.006
Whitesell L. , Lindquist S. 2009 Inhibiting the transcription factor HSF1 as an anticancer strategy Expert Opin. Ther. Targets 13 469 - 478    DOI : 10.1517/14728220902832697
Wolfers J. , Lozier A. , Raposo G. , Regnault A. , Thery C. , Masurier C. , Flament C. , Pouzieux S. , Faure F. , Tursz T. , Angevin E. , Amigorena S. , Zitvogel L. 2001 Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming Nat. Med. 7 297 - 303    DOI : 10.1038/85438
Wust P. , Hildebrandt B. , Sreenivasa G. , Rau B. , Gellermann J. , Riess H. , Felix R. , Schlag P. M. 2002 Hyperthermia in combined treatment of cancer Lancet Oncol. 3 487 - 497    DOI : 10.1016/S1470-2045(02)00818-5
Yang H. X. , Mitchel R. E. 1991 Hyperthermic inactivation, recovery and induced thermotolerance of human natural killer cell lytic function Int. J. Hyperthermia 7 35 - 49    DOI : 10.3109/02656739109004975
Yao Y. , Wang C. , Wei W. , Shen C. , Deng X. , Chen L. , Ma L. , Hao S. 2014 Dendritic cells pulsed with leukemia cell-derived exosomes more efficiently induce antileukemic immunities PLoS One 9 e91463 -    DOI : 10.1371/journal.pone.0091463
Zhang Y. , Huang L. , Zhang J. , Moskophidis D. , Mivechi N. F. 2002 Targeted disruption of hsf1 leads to lack of thermotolerance and defines tissue-specific regulation for stress-inducible Hsp molecular chaperones J. Cell Biochem. 86 376 - 393    DOI : 10.1002/jcb.10232