In this review, we summarized the historical and experimental basis of cancer immunity and the role of fever and of artificial elevation of temperature on immunity. The interactions of heat in vitro and in vivo on cytotoxicity of immune competent cells are discussed as their positive contribution on the various cancer mmunotherapeutic strategies. Furthermore we have described the link existing among Heat shock proteins, Toll like receptors and innate immunity justifying the use of temperature elevation for treating cancer. The disputed and life threatening effect of local and whole body hyperthermia on metastasization is also reviewed.

Introduction

The role of the immune system in eradicating malignant cells is not yet clarified, however spontaneous regression of some cancers has been demonstrated to be associated to the induction of fever and activation of immunity.^1-3 The crucial importance of fever in these regressions justifies the attempt to induce artificial thermal elevation of body temperature (hyperthermia) for mimicking natural fever effects on cancer.^3-7

Tumor Immunity

Background

Tumor regression in vivo is mediated by a complex interplay between two main mechanisms: innate and adaptive immune response (Tables 1, 2), that is involved with the immune recognition of cancer cells. Innate mechanism [involving soluble and cellular components (Table 1)^8-10 may trigger inflammatory events in the tumor microenvironment and in presence of a local adequate cytokine combination (IL-2, IL-12, IL-18, IL-23), stimulate dendritic cells (DCs),¹¹ the most specialized antigen presenting cells (APCs), to react against tumor specific surface antigens (TAAs).^12-16 After engulfment by DCs, TAAs are presented to naive T cells associated to Major Histocompatibility complex (MHC).¹⁶ Naive T cells activation occurs when the antigenic peptide-MHC complex interacts with the T Cell Receptor (TCR). However TCR receptor binding is not sufficient for a full activation of T cells unless costimulatory molecules interact with the specific ligands on the surface of APC. The presence or absence of costimulatory signals like B7-1(CD80), B7-2(CD86) and CD40/CD40L), determines whether immune response becomes anergic or tolerant. CD40/CD40L is expressed transiently following TCR activation on the surface of CD4⁺ cells and it is a key molecule in mediating the activation of B cells and in controlling CD8 T cells. Antigens can be associated to MHC I or MHC II class complexes and are presented by DCs to TCR of CD8⁺ and CD4⁺ T cells, respectively associated to the proper costimulatory molecules (fig. 1). Both CD4⁺ and CD8⁺ cells after activation and costimulation produce a series of cytokines that differentiate T-Helper (CD4₊) lymphocytes in two subpopulations (T_H 1, T_H 2 cells). TH 1 cells produce IL-2, IFN-γ, TNF-α and granulocyte macrophage colony stimulating factor (GM-CSF) that increase the activity of macrophages, and the expression of MHC class 1 molecules on the surfaces of CD8⁺ cells. T_H 2 secretes another group of cytokines IL-4, IL-5 and IL-10, that induces naive B cells to produce antibodies. The shifting towards T_H 2 pattern has recently been associated with an increased tumor metastasisation and a decreased survival in many human and animal neoplasia (fig. 4).^12,14,17,18

Table 1

Principal cellular and soluble antitumoral components of innate immune system.

Table 2

Principal antitumoral components of adaptive immune system.

Figure 1

In this diagram the various mechanisms elicited by stress for stimulating innate and adaptive immunity against cancer are illustrated. DCs= dendritic cells; CTL= cytotoxic T lymphocytes; TCR= T-cell receptor; MHC= major histocompatibility complex; Abs= (more...)

Figure 4

After heat stress the HSPs can induce tumor immunity by two mechanisms: Increasing Antigen presentation through CD91 receptors, or by TLRs receptors.

CD8+, cytotoxic T cells (CTLs) are the major effectors of tumor regression;¹⁹ however, CD4+T cells collaborate to their activation. Once activated CTLs do not need costimulation, since MHC-1-bound antigen is sufficient. For eliminating target cells (neoplastic cells) CTLs use three effector molecules: Perforins, Granzyme and Fas ligand. Associated to these killing mechanisms, CTLs secrete specific cytokines, such as: IFN-γ, TNF-α and TNF-β. This pattern of cytokines plays an important role in the activation of macrophages which can exert a direct tumor cytotoxic or, conversely, stimulate tumor progression, depending on the tumor microenvironment.²⁰

Other cells morphologically and functionally distinct, such as Natural Killer cells (NKs), macrophages and neutrophils, use pattern-recognition receptors and other cell-surface molecules to detect tumor cells directly.^8,20 Differently from T cells, NKs inhibit tumor growth in a MHC-non restricted manner. Frequently tumor cells (like stressed cells) express on their surfaces different glycoproteins (MICA and MICB) which function as ligands for NKG2D receptors on NK cells. Once activated, these receptors stimulate NK cell activity.²¹ By contrast, DCs use CD36 and α_vβ₅ integrin to recognize and phagocytize apoptotic tumor cells. Apoptotic tumor cells in turn release Heat Shock Proteins that, after specific interaction with CD91 receptors on DCs, induce their maturation: thus providing a tailored immune response (See: fig. 1 and fig. 4).²²

Therapeutic Modalities

Immunotherapy may be either active or passive, specific or nonspecific depending on the process of host immune system stimulation, (see Table 3).^16,54,55

Table 3

Classification of cancer immunotherapy.

Active Specific Immunotherapy (Vaccine, Gene Therapy, Heat Shock Proteins)

Serological identification of antigens by recombinant expression cloning technique (SEREX) has recently permitted to detect more than 1500 TAAs holding a specific antitumor activity.^52,56

Tumour vaccination (TV) is a therapeutic form of therapy involving patients with detectable disease and it is used for triggering a robust, appropriate and specific immune response towards a well characterized TAAs, avoiding immune-tolerance and providing a long lasting immune response.^52,57 The first tumor vaccines were obtained by irradiating tumor cells. The obtained results were not enthusiastic, inducing several authors to combine tumor vaccines with nonspecific immune modulators, such as BCG, New Castle Disease virus (NDV) and Detox; however the survival rate was comparable to the group treated with chemotherapy. To ameliorate the results, newer vaccines, including allogenic or autologous tumor cells, were genetically manipulated in order to produce a stronger immune response. Tumor cells, were encoded with different cytokines, however only those engineered to produce GM-CSF proved to induce tumor rejection.⁵⁸

A large number of clinical trials, involving different strategies, are actually being conducted and have been reviewed elsewere.^54,58-62

Some of them will however be discussed for a positive interaction with hyperthermia treatment (see Table 7). These are: dendritic cells, gene therapy and heat shock proteins.

Table 7

Effects of WBHT and LHT on different immune treatment modalities.

Dendritic Cells (DCs)

Are a distinct population of leukocytes that play a crucial role as antigen presenting cells and as initiator of antitumor immunity.⁵⁹ DCs reside mainly in peripheral nonlymphoid tissue, after antigen uptake; however they migrate to the draining lymph node to present antigens to T cells. Preclinical studies have demonstrated that antigen pulsed DCs can generate a potent antitumor activity.^63,64 DCs are artificially loaded with antigens by different techniques and can stimulate both innate and adaptive immune system.^63,64 Many clinical trials, testing dendritic cell-based vaccines are in progress and have proved a partial clinical efficacy.^65,66 In every case, preclinical studies have also demonstrated that the direct intratumoral injection of ex vivo—generated DCs can avoid the need for a tumour antigen loading ex vivo by improving antigen presentation or migration to lymph nodes. A required condition is that injected DCs must be genetically modified in vitro to produce cytokines and chemokines, such as: IL-2, IL-7, IL-12, CD40L, GM-CSF, lymphotactin or secondary lymphoid tissue chemokine (SLC).^67,68 The presence of these cytokines may render DCs more able to capture and process TAAs. This overcomes the increased immune suppressive factors (IL-10, VEGF and TGF_β PGE₂) present in the tumour medium.^69-72

Gene Therapy

Is defined as the method of delivering genetic material into a cell, by altering the cellular phenotype permanently or transiently.⁷³

The efficient and precise targeting of a gene to specific cells or tissues remains the technical hurdle of gene therapy. The delivering methods consist in use of viral or nonviral vectors and in vivo or ex vivo gene therapy approach.⁷⁴ The ex vivo approach involves the removal of patient's own cells and the readministration after genetic modification. By contrary, in vivo, therapy involves the direct injection of genetic material into patients.

The most promising designed vectors for in vivo therapy are viral vectors. The viral vectors enter into cells by receptor mediated endocytosis and escape from endosomes after DNA delivery to nuclei. They have some disadvantages such as: (a) patient immune recognition of viral proteins with a consequent immune attack and destruction of infected cells, (b) restriction in size and quantity of transgene, (c) inability of repeated viral administration.^75,76 Most clinical studies have been carried out using retroviruses or adenoviruses as transfer vector with various advantages and disadvantages.^77,78 The targets of viral therapy can be: inactivation of oncogenes (i.e., ras, c-myc, c-erB-2, abl, bcl-2);⁷⁷ genes involved in tumor progression (i.e., Triple —helix formation); immunomodulatory genes encoding cytokines (TNF-α,IL-2; GM-CSF, INF-γ) costimulatory molecules (i.e., MCH molecules, CD40ligand. B7, Cd28);⁷⁶ angiogenic factors (i.e., VEGF)^70,75 and tumor associated antigen genes.⁷⁹

Non viral vectors (naked DNA, lipids, liposome) make use of physical methods of gene transfer. They are free of the side effects of viral vectors, but they suffer of specificity.⁷⁵ Ex vivo gene delivery is the best system for such vectors. Naked DNA in the form of plasmid can be injected into muscle tissues or conjugated with gold particles and bombarded into the tissues. Muscle tissue injection is the most effective delivery method of administration. Repeated injections determine an improvement in therapeutic gene expression but the effect does not last for long.^75,77

Another route of DNA administration is the use of lipid vehicles. Two classes of lipid aggregates have been used : (1) cationic lipids [lipoplexes]; (2) stabilized liposomes. Lipoplexes are positively charged and interact with negatively charged DNA forming a stable complex. As outlined by Clark,⁸⁰ cationic lipids have many benefits, such as: easy and inexpensive way of production, non toxicity and potential of delivering large quantity of polynucleotides into cells. However, in order to develop commercially these vector systems, several barriers must be overcome, especially formulation and stability of manufacture.⁸⁰ The presence of an excessive number of particles positively charged favour precipitation and aggregation. To circumvent this problem of flocculation, hydrophilic polymers like polyethylene glycol polymers (PEG) have been created.⁸⁰ These sterically stabilized liposomes (PEG liposomes) allow efficient encapsulation of DNA and oligonucletides. They also permit to prepare well-defined and uniform particles suitable for drug carrier.^81,82 Furthermore PEG liposomes show an improvement in half life time due to a reduced renal and cellular cleareance. Also they show an enhanced protection from proteolysis with reduction of toxicity.^81,82 Other types of liposomes based on polyethyleneimine (PEI) have proved to be stable to nebulization and to be efficiently delivered as aerosol DNA plasmids to lung parenchyma,^83,84 exhibiting a greater concentration into lungs when compared to other route of administration such as intravenous route.^84,85

Concluding, vaccine therapy is a tailored specific therapy. However, critical issues to overcome are the choice of the delivery system and the identification of singular epitopes.

Heat Shock Proteins

Meet the request for searching specific epitopes. In fact, they have been implicated at multiple points in the immune response, including initiation of proinflammatory cytokine production, antigen recognition and processing, and phenotypic maturation of DCs.⁸⁶ A preliminary clinical study on colorectal tumor metastasised to liver treated with autologous HSP-96, has clearly demonstrated important points.⁸⁶ Namely, HSP-complex induced a significant increase in committed lymphocytes, as response patients have a better clinical outcome as overall survival and as disease free survival and no toxicity was observed.^46,87 The importance of hyperthermia in generating HSPs with the aim of immunization will be described later.

Active Non Specific Immune Therapies: Coley Toxins (CTs)

In 1868 W. Busch in Germany concluded that fever induced by certain bacteria from erysipelas can cause tumor regression or cure cancer. This was suggested after the observations on a patient with a soft tissue sarcoma of the neck infected by erysipelas.^3,4 The causative agent (streptococcus) at that time was not identified. Subsequently, in 1892, a young American surgeon W. B. Coley, unaware of Busch's findings, observed a regression of soft tissue sarcomas in a patient infected by erysipelas. Stunned by that finding, he searched the medical literature and found many publications confirming his observation.^4,5 Coley prepared initially a culture of streptococci that he injected at the tumor site with encouraging results. He even noted that the presence of Serratia Marcenscens could enhance the virulence of streptococci and an injection remote from the tumor site could equally result in tumor regression. After these observations Coley incorporated Serratia Marcenscens into the streptococcal vaccine just obtaining the so called “Coley's toxin” or “Mixed Bacterial Vaccine” (MBV). The intravenous route was the most effective; the toxin dose was considered sufficient only if accompanied by fever (39-40°C). Fever and the sustained pyrexia, now recognized to be elicited by tumor necrosis alpha (TNF-α) and by other cytokines.^1,2,3,5 Were considered the critical points in the tumor regression.^4,5 It was also observed that those who developed the highest fever were most often the ones with the longest survival.

Coley should be considered the first scientist to apply with a certain continuity, induced hyperthermia (fever) as immune treatment.^1,3,6 He noted that tumor regression was obtained only in presence of fever. Since then the interaction between hyperthermia (in whatever way obtained) and immunity has not been completely elucidated.⁷

To our opinion, a better comprehension of the effects of heat on immunity is obtained by understanding the effects of thermal component of fever on immunity (see Table 4).

Table 4

Effects of thermal component of fever on innate and adaptive immunity.

Effects of Thermal Component of Fever on Immune System

Often, in presence of tumor and microrganisms host replies by increasing body temperature. ^1-3

Fever is a complex neuroendocrine adaptive response due to an increase in the set - point temperature regulator found in hypothalamic area.⁸⁸ After their entry into organism, bacteria or viruses induce macrophages to produce a series of proinflammatory cytokines such as: interleukins (ILs) -1,2,6, tumor necrosis factor alpha (TNF-α), Interferon - α (IFN-α), IFN-γ. These cytokines, with an additional mediator [prostaglandin E₂ (PG E₂) cyclooxygenase 2 prostaglandins derivate (COX-2)], act on the thermoregulatory area and reset it to a higher level of temperature, producing the febrile response.^89-91 Temperature elevation has been suggested to be beneficial for the host.^92,93 It is unlikely that evolution has maintained such an expensive defensive metabolic mechanism, without a role.^2,3 However, the role of temperature on immune defence is not completely understood. Different studies support the idea that temperature rise has a beneficial role, such as an improved efficiency of macrophage killing activity and an increase on survival in mice infected by herpes virus or with rabies.^94-96

Leukocyte adhesion to endothelium and emigration to the site of inflammation are positively affected by heat as the antigen-non specific defence systems (chemotaxis, phagocytosis, complement haemolysis) (see fig. 2 and fig. 3).⁹⁷ Even antigen-specific activation, proliferation, cytokine expression differentiation and antibody secretion by lymphocytes are affected by temperature. T cell responsiveness to mitogens, IL-1, IL-2 and antigens increase linearly until a temperature of 39°C; beyond this limit a decline is observed.^96-98 Furthermore, it has been shown that antibody secretion in vitro is temperature dependent and this effect declines in the absence of T-helper cells.⁹⁷

Figure 2

Time-dependent exemplary induction of IL-1 in a patient after induction of fever up to 39.8°C with a biological pyrogen (Vaccineurin®).

Figure 3

Emigration, homing, proliferation and activation of leukocytes in a patient after induction of fever up to 39.8°C with a biological pyrogen (Vaccineurin®) depending on time.

A summary of temperature effect on specific and non specific immunity is presented in Table 4. From it you can conclude, that temperature on the order of fever range (39-40°C) is the most favourable ones for the immune response.^94,96,97 The effects of hyperthermia on the immune system are complex and pleiotropic and are dependent on temperature, time and microenvironment.

Effects of Induced Thermal Elevation (Hyperthermia) on Immunity

Temperature application above the physiologic range (≥ 42.5°C) has been demonstrated to induce various effects on immune system (see Tables 5, 6).^6,7,99-103

Table 5

Effects of WBHT, and LHT on immune response.

Table 6

Effects of fever, WBHT, LHT on cytokines induction and activity.

Specific Effects of Hyperthermia on Immune Therapeutic Modalities

Several recent studies, suggest that hyperthermia is suitable as a complementary therapeutic modality for immunotherapy, (see Tables 6 and 7).

Effects of Hyperthermia on Lymphocyte Homing

As previous mentioned, leukocyte infiltration into tumor mass is mediated by the expression of various adhesion molecules and cytokines.^172,173 Among these adhesion molecules, ICAM-1 and α₄β7 integrin are pivotal in regulation of the migration of leukocytes from the blood vessels.²⁰ Their expression has been demonstrated to decrease in presence of VEGF,^28,29 to increase in presence of febrile range temperature (38-40°C) and INF-α.^136,174 In fact, there is an increasing evidence that local and whole body hyperthermia can enhance both L-selectin lymphocyte-endothelial cell adhesion.^130,136,175 Regarding increase of adhesion molecules it appears that hyperthermia differs compared to other therapies. In fact the increase has been detected only on tumors microvasculature and on peritumor lymphatic not on surrounding normal vasculature.¹⁷⁶ The mechanism underlying HT control of L-selectin have revealed that febrile temperature do not increase lymphocyte L-selectin surface density or L-selectin dependent recognition of soluble carbohydrates but the avidity of preexisting adhesion molecules for physiologic ligands.¹⁷⁶ This up regulation of adhesion process suggests the use of LHT and WBHT in clinical settings for delivering selectively cytotoxic T-cells or gene armed lymphocytes only into the tumor area.

The Danger Model and Hyperthermia-Effects on Dendritic Cell Maturation and Stimulation of Innate-Adaptive Immunity

During the last decade, we have learned a great deal about the molecular mechanisms responsible for the modulation of tumor immunity; however, little advances have been made clinically so far. The reasons for this failure may be the result of several mechanisms:

1. not complete control of tumor microenvironment¹⁷⁷
2. non-appropriate presentation of antigens¹⁷⁸
3. innate immunity not adequately stimulated or suppressed¹⁷⁹
4. tumor immune evasion.

Hyperthermia has a role in controlling the first three mechanisms. Inside a tumor mass, it exists at least partially a stressful hypoxic and acidic micro milieu which hampers antigen presentation or immune effectors function.^26,180 On one hand, this kind of stressful environment can modify the response of lymphocytes [in vitro] to synthesis and release of mitogens and cytokines during HT treatment,¹⁰¹ on the other part it is the more suitable for killing tumor cells by heat, and for the generation of the “Danger Signal”.¹⁷⁸

Effects of Hyperthermia on Metastatic Process

Metastatic process is the most fearsome aspect of cancer. The formation of metastases is a complex multistep process influenced by the host and by selection and resistance induced by the different therapeutic approaches used.^207,208 Shah outlined in animal experiments that a sublethal heating (≤ 42.5°C) of tumors with a non-complete destruction of all cancer cells, may enhance metastases formation, in a way not dissimilar to chemo- and radiotherapy.²⁰⁹ In 1974, studies by Dickson and Ellis²¹⁰ opened a great controversy on the efficacy of hyperthermia treatment, in fact they reported an increased metastasization to the liver following heating of a Yoshida sarcoma in rats. Further studies reported by Shah²⁰⁹ showed an increased metastasization preferentially to lymph nodes and lungs following a non appropriate heating. A curative treatment with appropriate temperature (≥ 42.5 °C) was associated to regression of primary tumor and was accompanied by increased host immunocompetence. An increase on metastization has been reported by some Authors and attributed to a decreased activity of NK cells.^6,7,106 Recent studies using WBHT in humans and animals²¹¹ did not found a decreased activity of NKs and CD4 cells in vivo, contradicting old studies in vitro.¹²¹ Urano,²¹² Dickson and Shah⁶ observed that WBHT may induce metastases at a frequency higher than LHT. Urano et al revealed that the size of the tumor and not its immunogenicity was critical for metastasization during WBHT.²¹² To reduce this incidence Oda et al²¹³ suggest the use of anticancer drugs associated to WBHT. Dickson and Shah⁶ reported the abrogation of the effects on immune response generated by curative local heating providing that WBHT was followed or was associated with local hyperthermia. More recent clinical studies on animals with melanoma, treated with Radiation alone or combined with LHT, have demonstrated no significant difference in metastasization between the two groups, though local recurrence was a common event and was associated with metastases appearance.^214,215 Similar phase III trial on human melanomas treated using similar design has shown an improved local control and a reduced metastasization with combined RT+LHT.²¹⁶ A recent randomised study on soft tissue osteosarcoma has demonstrated that the rate of metastasization with thermoradiotherapy is similar to that seen with preoperative radiation therapy alone.²¹⁵ Similar conclusions about dissemination of malignant cells during WBHT in combination with chemotherapy for epithelial malignancies have been reached by Hegewisch-Becker and collaborators.²¹⁶

In order to obtain a maximum benefit from tumor heating a functioning host immune response seems necessary. In fact, studies conducted in the late 1990 by Pontiggia et al²¹⁷ have clearly demonstrated that patients with higher values of inflammatory tests (α2 glycoprotein > 1.0 g/l; high sedimentation rate > 50/1h, and with a lymphocytes count < 500/mc, and a ratio CD4/CD8 < 1.2) failed to obtain remission. The same authors outlined that patients responsive to BRM (i.e., INF-α) show an increase in NK cell number and responders have a better prognosis as compared to non responders.²¹⁷

Another important phenomena to take into consideration is the abscopal response. It consists in a regression of tumor at other anatomic sites following curative heating of primary tumor. This phenomena has been described in animals and humans.^99,213 Disappearance of primary tumor and regression of distant metastases after hyperthermic limb perfusion in both sarcoma and melanoma has been ascribed to a non specific immune reaction, such as inflammatory reaction with an increased macrophage infiltrate.^{45,96,99,103,106} Clinical studies by Shah²⁰⁹ and Dickson²¹⁰ have not demonstrated distant metastases regression after primary tumor treatment with LHT. Abscopal phenomena seems not pertinent to WBH treatment.

Conclusions and Comments

Tumor regression of some type of human tumors following HT has been reported. The evidence of an involvement of tumor immune response in this regression due to temperature elevation is increasing step by step.

The effects of hyperthermia on the immune system are pleiotropic.⁷ First of all, the compartment shifting and homing of immune competent cells (T-lymphocytes) and neutrophils to tumor area is increased whereas cytotoxicity is only transitorily affected.¹³⁰ The increase of temperature correlates positively with an increased phagocytosis of leukocytes and macrophages within fever range temperatures.^127,173 B-cells are activated by heat which brings about an increase of the production of immunoglobulins. On the contrary NK cells cytotoxicity is suppressed and their activity more affected in vitro.^{116,121,218-220} This suppression is however temporary. In the range of temperature beyond 39° after a period of stunning a complete recovery follows. Some authors have also demonstrated that recovery can be augmented or cytotoxicity partially spared by using interferons^220,221 or antioxidants¹¹³ such as superoxide dismutase. A summary of the effects of LHT and WBH on LAK cell and NK cells cytotoxicity can be found in Table 8. From these studies some aspects become evident:

1. Temperature is crucial.
2. WBH affects less the cytoxicity activity of both immunocompetent cells than LHT.
3. Times of exposure to heat in vitro studies are not clinically comparable.

Table 8

Effects of WBHT, LHT on cellular immune response.

In fact different parameters can influence lymphocyte reaction in vitro compared to in vivo situation. They are: a) treatment time that is too long (3-4h; 18h) or too short (1/2 h), b) the different lytic E:T ratio, c) the nonuniform distribution of heat easily obtainable in vitro but not in vivo and d) the pH of the medium. Studies by Skeen et al have tried to reproduce tumor pH microenvironment and its effect on lymphocytes. They have demonstrated that the pH of the medium (obtained adding lactic acid) had no effect at 37°C but showed a synergistic impairment with heat at 41,42 and 43°C.¹⁰¹

These examples indicate experiments are to be conducted with appropriate methods for assessing in vitro and in vivo cellular immune response. We also suggest to employ experimental conditions well defined, standardized and nearer the clinical situation for better understanding HT effect on immunity. In particular: pH of medium, Cytokine assay in situ, activation and impairment of cellular response by DCs use. Comprehensive clinical studies on WBHT are to our opinion those of Robins and Atanactovic.^{103,121,123,125,127}

CD4+ / CD8+ lymphocytes ratio does not change in vivo, whereas activation and maturation of Dendritic Cells is positively affected.⁴³ In fact, in animals experiments, febrile range temperature elevation (39.5°C-41°C) have demonstrated to elicit DCs maturation through HSPs induction. Furthermore, for this order of heating WBHT induces a panel of cytokines similar to that induced during fever;^221,222 on the contrary LHT is not able to elicit any cytokines production.¹²² (see Table 6).

The induction of HSPs is rapid and occurs immediately following exposure to only a few degrees above normal physiological temperature stimulation.²²³ HSPs induction occurs during hyperthermia treatment and represents a simple method for stimulating innate immunity^9,40 and for harness a highly tailored cancer immunotherapy eliciting the maturation of Dendritic cells and their recruitment into the tumor area.^{106,130,132,133} In fact, tumor antigens presentation by HSPs isolated from cancer cells has been shown to induce a specific and individualized protective anti tumor response.⁸⁷ The tissue specificity of HSPs relies on the fact that they can bind antigenic peptides and improve endocytosis of the chaperoned peptides by APCs, enhancing their ability to stimulate peptide-specific T cells.^224,225

Regarding the effects of hyperthermia on metastatic dissemination the conclusions are still controversial and many bias are linked to in vitro and in vivo assays for monitoring cancer immune response. However clinical studies on moderate (fever range) and extreme WBHT seem to provide the evidence for a non significant metastatic spread. Concluding, positive and negative effects on immunity are produced by HT treatment and are summarized in Table 9. A positive association between hyperthermia and the various therapeutic strategies has been demonstrated, suggesting a use in conjunction with a stimulation of a tumor immunity such as : cytokines, monoclonal antibodies, gene therapy, dendritic cells administration (see Tables 6, 7, 8). The recent recognized involvement in innate immune response, increases further the interest of hyperthermia, but increase the regret for the time missed abandoning Coley's Toxin and Mixed Bacterial Vaccine too.

Table 9

Positive and negative effects of hyperthermia on immunity.

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