Abstract
BackgroundThe treatment of intratumoral dentritic cells (DCs) commonly fails because it cannot evoke immunity in a poor tumor microenvironment (TME). Modulated electro-hyperthermia (mEHT, trade-name: oncothermia) represents a significant technological advancement in the hyperthermia field, allowing the autofocusing of electromagnetic power on a cell membrane to generate massive apoptosis. This approach turns local immunogenic cancer cell death (apoptosis) into a systemic anti-tumor immune response and may be implemented by treatment with intratumoral DCs.MethodsThe CT26 murine colorectal cancer model was used in this investigation. The inhibition of growth of the tumor and the systemic anti-tumor immune response were measured. The tumor was heated to a core temperature of 42 °C for 30 min. The matured synergetic DCs were intratumorally injected 24 h following mEHT was applied.ResultsmEHT induced significant apoptosis and enhanced the release of heat shock protein70 (Hsp70) in CT26 tumors. Treatment with mEHT-DCs significantly inhibited CT26 tumor growth, relative to DCs alone or mEHT alone. The secondary tumor protection effect upon rechallenging was observed in mice that were treated with mEHT-DCs. Immunohistochemical staining of CD45 and F4/80 revealed that mEHT-DC treatment increased the number of leukocytes and macrophages. Most interestingly, mEHT also induced infiltrations of eosinophil, which has recently been reported to be an orchestrator of a specific T cell response. Cytotoxic T cell assay and ELISpot assay revealed a tumor-specific T cell activity.ConclusionsThis study demonstrated that mEHT induces tumor cell apoptosis and enhances the release of Hsp70 from heated tumor cells, unlike conventional hyperthermia. mEHT can create a favorable tumor microenvironment for an immunological chain reaction that improves the success rate of intratumoral DC immunotherapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1690-2) contains supplementary material, which is available to authorized users.
Highlights
The treatment of intratumoral dentritic cells (DCs) commonly fails because it cannot evoke immunity in a poor tumor microenvironment (TME)
Results Modulated electro-hyperthermia treatment (mEHT) induced more apoptotic cell death than water bath-induced hyperthermia in CT26 cells The apoptotic efficacy of hyperthermia that was induced by a water bath or mEHT in CT26 cells was evaluated using an apoptosis assay kit. mEHT treatment significantly increased the percentage of apoptotic cells
MEHT promoted the generation and release of heat shock protein70 (Hsp70) in CT26 cells Since the expression of Hsp70 is a characteristic of hyperthermia treatment, the intracellular amount of Hsp70 and the release of Hsp70 following mEHT and water bath-induced hyperthermia were investigated
Summary
The treatment of intratumoral dentritic cells (DCs) commonly fails because it cannot evoke immunity in a poor tumor microenvironment (TME). Modulated electro-hyperthermia (mEHT, trade-name: oncothermia) represents a significant technological advancement in the hyperthermia field, allowing the autofocusing of electromagnetic power on a cell membrane to generate massive apoptosis This approach turns local immunogenic cancer cell death (apoptosis) into a systemic anti-tumor immune response and may be implemented by treatment with intratumoral DCs. The tumor microenvironment (TME) is an important factor in successful local treatment and in provoking a systemic immunological response in cancer patients [1]. The function of DCs is mainly positively affected by a microenvironment that contains fewer immune suppression factors, more immune potentiating factors and an immunogenic hub in the tumor site [5, 6] This fact previously motivated us to develop a new strategy to improve the efficacy of in situ DC vaccination by adding combining heat shock protein (Hsp) [7] or by electro-gene therapy with cytokine [8]. A favorable TME can provide the various important functional immunological cells and cytokines that are required for immunotherapy [10, 11]
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