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HSP70 did not activate NK cells directly. Instead, HSP70 induced the expression of an NKG2D ligand MICA on DCs, which then activated NK cells in an NKG2D-dependent manner.

DCs are the most powerful professional antigen presenting cells (APCs) that are instrumental in processing antigens and orchestrating antigen-specific adaptive immunity and tolerance

NK cells and DCs can functionally interact with each other both in vitro and in vivo

autologous HSP70 could stimulate significant IFN-γ production

The magnitude of the IFN-γ response was different from patient to patient and correlated with the number of functional NK cells

In addition, 10 out of 14 patients had significantly increased IFN-γ producing cells in the peripheral blood after HSP70 vaccinations, which is again in line with increased NK cell activity as reported in our original study in these patients

Clinical studies of DCA have shown reduced lactate levels

It has been reported that DCA activates the PDH by inhibition of PDK in a dose-dependent manner, and results in increased delivery of pyruvate into the mitochondria

The antitumor activity of DCA on nonsmall cell lung cancer, breast cancer, glioblastomas, and endometrial and prostate cancer cells has been demonstrated

It is well known that many chemotherapeutic agents have a low therapeutic index in brain tumors.

The most common metabolic hallmark of cancer cells is their propensity to metabolize glucose to lactic acid at a high rate even in the presence of oxygen

Pyruvate dehydrogenase kinase (PDK) is a gate-keeping enzyme that regulates the flux of carbohydrates (pyruvate) into the mitochondria

In the presence of activated PDK, pyruvate dehydrogenase (PDH), a critical enzyme that converts pyruvate to acetyl-CoA instead of lactate in glycolysis, is inhibited, limiting the entry of pyruvate into the mitochondria.

the level of Hsp70 was significantly decreased

DCA can penetrate the BBB

It has been reported that DCA treatment resulted in an increase in the proportion of tumor cells in the S phase, showing a decrease in proliferation as well as the induction of apoptosis

Heat shock proteins (HSPs) are involved in protein folding, aggregation, transport, and/or stabilization by acting as a molecular chaperone, leading to the inhibition of apoptosis by both caspase-dependent and/or independent pathways

HSPs are overexpressed in a wide range of human cancers and are implicated in tumor cell proliferation, differentiation, invasion, and metastasis

Considering the fact that high expression of HSPs is essential for cancer survival, the inhibition of HSPs is an important strategy of anticancer therapy.

In addition, after 5 years of continued treatment with oral DCA at a dose of 25 mg/kg, the serum DCA levels are only slightly increased compared with the levels after the first several doses, also showing its safety for oral administration at this dose.

DCA can enter the circulation rapidly after oral administration and then generate the stimulation of PDH activity generally within minutes.

Our in vivo results in tumor tissues indicated that DCA significantly induced ROS production and decreased MMP in tumor tissues

The numbers of microvessels in the DCA treatment groups were significantly decreased, suggesting the potential antiangiogenic effect of DCA

Under hypoxic conditions, hypoxia-inducible factor (HIF-1α) is activated and induces angiogenesis

In addition, HIF-1α can also induce the expression of PDK,48 which can inhibit the activity of PDH

The inhibition effect of DCA on HIF-1α would decrease vascular endothelial growth factor and inhibit angiogenesis

the antiangiogenic effect in the 25 mg/kg treatment group was lower than that in 75 mg/kg or 125 mg/kg treatment groups

In conclusion, DCA induces the apoptosis of C6 cells through the activation of the mitochondrial pathway, arresting the cell cycle of C6 cells in S phase and down-regulating Hsp70 expression.

DCA significantly induced the ROS production and decreased the MMP in tumor tissues. Our in vivo antitumor activity results also indicated that DCA has an antiangiogenic effect

Hyperthermia differs fundamentally from fever in that it elevates the core body temperature without changing the physiological set point

hyperthermia is induced by increasing the heat load and/or inactivating heat dissipation

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

mild temperature hyperthermia (ie, within the fever-range, 39–41°C)

moderate hyperthermia (41°C)

Hsps are a family of stress-induced proteins

they are key regulators of cellular protein activity, turnover and trafficking

Hsps ensure appropriate post-translational protein folding, and are able to refold denatured proteins, or mark irreversibly damaged proteins for destruction

the ability of fever-range hyperthermia to induce reactive immunity against tumor antigens through DCs and NK-cells is likely mediated by Hsps

thermotolerance

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

Hsps released from stressed or dying cells activate dendritic cells (DCs), transforming them into mature APCs

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

In several models of hyperthermia, heat-treated tumors exhibited improved DC priming and generation of systemic immunity to tumor cell

hyperthermia alone can enhance antigen display by tumor cells, thus rendering them even more susceptible to programmed immune clearance

Fever-range hyperthermia may also induce Hsps

Hsps may exert an adjuvant effect by bolstering MHC class II and co-stimulatory molecule expression by DCs

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

specific Hsp, Hsp70, directly inhibits apoptosis pathways in cancer cells, as demonstrated in human pancreatic, prostate and gastric cancer cells

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

It has been reported that Hsps are generated from necrotic tumor cell lysates, but not from tumor cells undergoing apoptosis

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

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.

support the use of hyperthermia as an inducer of Hsps to serve as ‘danger signals’, activating antitumor immune responses

whole-body hyperthermia not only augments immune responses, but also stimulates the migration of skin-derived DCs to draining lymph nodes

suggest a valuable role of hyperthermia in DC cancer vaccine strategies

In mice treated with fever-range whole-body hyperthermia, tumor growth was significantly inhibited and NK-cell infiltration increased

exposure to fever-range hyperthermia resulted in improved endogenous NK-cell cytotoxicity to several cancer types

improved activation and function of DCs and NK cells following hyperthermia

Hyperthermia increases the expression ICAM-1 a key adhesion molecule,

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.

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.

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

the ability of DCs present in the lymph nodes to stimulate an anti-tumor immune response is critical

hyperthermia has been shown to improve immune surveillance by T-cell

and to increase DC trafficking to lymph nodes