Hyperthermia as an immunotherapy strategy for cancer - 1 views
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the notion of treating human cancers with heat dates back to the writings of Hippocrates
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enhance the efficiency of standard cancer therapies, such as chemotherapy and radiation treatment
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After antigen uptake at tumor sites, APCs have the ability to create a robust response by entering lymphoid compartments and programming lymphocytes
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Hyperthermia differs fundamentally from fever in that it elevates the core body temperature without changing the physiological set point
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hyperthermia is induced by increasing the heat load and/or inactivating heat dissipation
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mor cells [2]. Although significant cell killing could be achieved by heating cells or tissues to temperatures > 42°C for 1 or more hours, the application, measurement and consistency of this temperature range within the setting of cancer clinical trials
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mild temperature hyperthermia (ie, within the fever-range, 39–41°C)
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moderate hyperthermia (41°C)
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Hsps are a family of stress-induced proteins
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they are key regulators of cellular protein activity, turnover and trafficking
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Hsps ensure appropriate post-translational protein folding, and are able to refold denatured proteins, or mark irreversibly damaged proteins for destruction
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the ability of fever-range hyperthermia to induce reactive immunity against tumor antigens through DCs and NK-cells is likely mediated by Hsps
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thermotolerance
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Hsps support the malignant phenotype of cancer cells by not only affecting the cells’ survival, but also participating in angiogenesis, invasion, metastasis and immortalization mechanisms
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Hsps released from stressed or dying cells activate dendritic cells (DCs), transforming them into mature APCs
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In theory, fever-range hyperthermia may take advantage of tumor cell Hsps by inducing their release from tumor cells and augmenting DC priming against tumor antigens
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In several models of hyperthermia, heat-treated tumors exhibited improved DC priming and generation of systemic immunity to tumor cell
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hyperthermia alone can enhance antigen display by tumor cells, thus rendering them even more susceptible to programmed immune clearance
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Fever-range hyperthermia may also induce Hsps
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Hsps may exert an adjuvant effect by bolstering MHC class II and co-stimulatory molecule expression by DCs
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thermal ablation of liver tumors in particular has demonstrated an ability to potentiate immune responses [57, 58] and elicit robust T-cell infiltrates at ablation sites
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specific Hsp, Hsp70, directly inhibits apoptosis pathways in cancer cells, as demonstrated in human pancreatic, prostate and gastric cancer cells
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Cross-priming is the ability of extracellular Hsps complexed to tumor peptides to be internalized and presented in the context of MHC class I molecules on APCs, thus allowing potent priming of CTLs against tumor antigens
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It has been reported that Hsps are generated from necrotic tumor cell lysates, but not from tumor cells undergoing apoptosis
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tumor cells exposed to hyperthermia in the heat shock range (42°C for 4h) prior to lysing, DC activation and cross-priming were significantly enhanced with the application of heat
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Due to the ability of Hsps to activate DCs directly by chaperoning tumor antigens upon their release [28], it is possible that both local and regional immune stimulation can be achieved with hyperthermia.
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support the use of hyperthermia as an inducer of Hsps to serve as ‘danger signals’, activating antitumor immune responses
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whole-body hyperthermia not only augments immune responses, but also stimulates the migration of skin-derived DCs to draining lymph nodes
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This allows for the activation of lymphocytes by the activated dendritic cells.
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suggest a valuable role of hyperthermia in DC cancer vaccine strategies
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In mice treated with fever-range whole-body hyperthermia, tumor growth was significantly inhibited and NK-cell infiltration increased
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Hyperthermia increased NK cell activation, proliferation, and infiltration, which equals increased cytotoxicity.
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exposure to fever-range hyperthermia resulted in improved endogenous NK-cell cytotoxicity to several cancer types
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improved activation and function of DCs and NK cells following hyperthermia
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Hyperthermia increases the expression ICAM-1 a key adhesion molecule,
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The combined effects of hyperthermia on lymphoid tissue endothelium and lymphocytes can promote immune surveillance and increase the probability of naive lymphocytes leaving the circulation and encountering their cognate antigen displayed by DCs in lymphoid organs.
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In independent clinical studies, whole-body hyperthermia resulted in a transient decrease in circulating lymphocytes in patients with advanced cancer [12, 94, 99, 100], a finding which mirrored observations in animal models in which lymphocyte entry into lymph noeds was increased following hyperthermia treatment [93]. Enhanced recruitment of lymphocytes to lymphoid tissues may be exploited in the treatment of malignancies.
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The initial tumor antigen presentation and initiation of clonal expansion of CTLs transpires in the lymph nodes and cannot take place outside this specialized compartment
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the ability of DCs present in the lymph nodes to stimulate an anti-tumor immune response is critical
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hyperthermia has been shown to improve immune surveillance by T-cell
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and to increase DC trafficking to lymph nodes