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BMC Cancer
Published in: BMC Cancer 1/2015

Open Access 01-12-2015 | Research article

Improving immunological tumor microenvironment using electro-hyperthermia followed by dendritic cell immunotherapy

Authors: Yuk-Wah Tsang, Cheng-Chung Huang, Kai-Lin Yang, Mau-Shin Chi, Hsin-Chien Chiang, Yu-Shan Wang, Gabor Andocs, Andras Szasz, Wen-Tyng Li, Kwan-Hwa Chi

Published in: BMC Cancer | Issue 1/2015

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Abstract

Background

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.

Methods

The 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.

Results

mEHT 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.

Conclusions

This 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.
Appendix
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Literature
1.
2.
Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392(6673):245–52.CrossRefPubMed
3.
Chi KH, Liu SJ, Li CP, Kuo HP, Wang YS, Chao Y, et al. Combination of conformal radiotherapy and intratumoral injection of adoptive dendritic cell immunotherapy in refractory hepatoma. J Immunother. 2005;28(2):129–35.CrossRefPubMed
4.
5.
Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, et al. Immunobiology of dendritic cells. Annu Rev Immunol. 2000;18:767–811.CrossRefPubMed
6.
Chi KH, Wang YS, Kao SJ. Improving radioresponse through modification of the tumor immunological microenvironment. Cancer Biother Radiopharm. 2012;27(1):6–11.CrossRefPubMed
7.
Wang YS, Liu SJ, Huang SC, Chang CC, Huang YC, Fong WL, et al. Recombinant heat shock protein 70 in combination with radiotherapy as a source of tumor antigens to improve dendritic cell immunotherapy. Front Oncol. 2012;2:149.PubMedPubMedCentral
8.
Chi CH, Wang YS, Lai YS, Chi KH. Anti-tumor effect of in vivo IL-2 and GM-CSF electrogene therapy in murine hepatoma model. Anticancer Res. 2003;23(1A):315–21.PubMed
9.
Wang YS, Tsang YW, Chi CH, Chang CC, Chu RM, Chi KH. Synergistic anti-tumor effect of combination radio- and immunotherapy by electro-gene therapy plus intra-tumor injection of dendritic cells. Cancer Lett. 2008;266(2):275–85.CrossRefPubMed
10.
Petrulio CA, Kim-Schulze S, Kaufman HL. The tumour microenvironment and implications for cancer immunotherapy. Expert Opin Biol Ther. 2006;6(7):671–84.CrossRefPubMed
11.
Kaufman HL. Manipulation of the Local Tumor Microenvironment for Cancer Immunotherapy. ASCO Education Book. 2004;23:165–71.
12.
Andocs G, Renner H, Balogh L, Fonyad L, Jakab C, Szasz A. Strong synergy of heat and modulated electromagnetic field in tumor cell killing. Strahlenther Onkol. 2009;185(2):120–6.CrossRefPubMed
13.
Szasz A, Vincze G, Szasz O, Szasz N. An Energy Analysis of Extracellular Hyperthermia. Electromagn Biol Med. 2003;22(2–3):103–15.CrossRef
14.
Andocs G, Szasz O, Szasz A. Oncothermia treatment of cancer: from the laboratory to clinic. Electromagn Biol Med. 2009;28(2):148–65.CrossRefPubMed
15.
Szasz A, Szasz N, Szasz O. Oncothermia: A New Kind of Oncologic Hyperthermia. In: Oncothermia: Principles and Practices. Netherlands: Springer; 2010. p. 173–392.CrossRef
16.
Szasz A, Vincze G. Dose concept of oncological hyperthermia: heat-equation considering the cell destruction. J Cancer Res Ther. 2006;2(4):171–81.CrossRefPubMed
17.
Hegyi G, Szigeti GP, Szasz A. Hyperthermia versus Oncothermia: Cellular Effects in Complementary Cancer Therapy. Evid Based Complement Alternat Med. 2013;2013:672873.CrossRefPubMedPubMedCentral
18.
Gadaleta-Caldarola G, Infusino S, Galise I, Ranieri G, Vinciarelli G, Fazio V, et al. Sorafenib and locoregional deep electro-hyperthermia in advanced hepatocellular carcinoma: A phase II study. Oncol lett. 2014;8(4):1783–7.PubMedPubMedCentral
19.
Fiorentini G, Giovanis P, Rossi S, Dentico P, Paola R, Turrisi G, et al. A phase II clinical study on relapsed malignant gliomas treated with electro-hyperthermia. In Vivo. 2006;20(6A):721–4.PubMed
20.
21.
Qin W, Akutsu Y, Andocs G, Suganami A, Hu X, Yusup G, et al. Modulated electro-hyperthermia enhances dendritic cell therapy through an abscopal effect in mice. Oncol Rep. 2014;32(6):2373–9.PubMed
22.
Dudek AM, Martin S, Garg AD, Agostinis P. Immature, Semi-Mature, and Fully Mature Dendritic Cells: Toward a DC-Cancer Cells Interface That Augments Anticancer Immunity. Front Immunol. 2013;4:438.CrossRefPubMedPubMedCentral
23.
24.
Mukhopadhaya A, Mendecki J, Dong X, Liu L, Kalnicki S, Garg M, et al. Localized Hyperthermia Combined with Intratumoral Dendritic Cells Induces Systemic Antitumor Immunity. Cancer Res. 2007;67(16):7798–806.CrossRefPubMed
25.
Friedman EJ. Immune modulation by ionizing radiation and its implications for cancer immunotherapy. Curr Pharm Des. 2002;8(19):1765–80.CrossRefPubMed
26.
Lugade AA, Sorensen EW, Gerber SA, Moran JP, Frelinger JG, Lord EM. Radiation-induced IFN-gamma production within the tumor microenvironment influences antitumor immunity. J Immunol. 2008;180(5):3132–9.CrossRefPubMed
27.
Teitz-Tennenbaum S, Li Q, Okuyama R, Davis MA, Sun R, Whitfield J, et al. Mechanisms involved in radiation enhancement of intratumoral dendritic cell therapy. J Immunother. 2008;31(4):345–58.CrossRefPubMedPubMedCentral
28.
Andocs G, Meggyeshazi N, Balogh L, Spisak S, Maros ME, Balla P, et al. Upregulation of heat shock proteins and the promotion of damage-associated molecular pattern signals in a colorectal cancer model by modulated electrohyperthermia. Cell Stress Chaperones. 2015;20(1):37–46.CrossRefPubMed
29.
Szasz A. Challenges and Solutions in Oncological Hyperthermia. Thermal Med. 2013;29(1):1–23.CrossRef
30.
Wang YS, Chi KH, Liao KW, Liu CC, Cheng CL, Lin YC, et al. Characterization of canine monocyte-derived dendritic cells with phenotypic and functional differentiation. Can J Vet Res. 2007;71(3):165–74.PubMedPubMedCentral
31.
Hirasawa M, Ito Y, Shibata MA, Otsuki Y. Mechanism of inflammation in murine eosinophilic myocarditis produced by adoptive transfer with ovalbumin challenge. Int Arch Allergy Immunol. 2007;142(1):28–39.CrossRefPubMed
32.
Huang AY, Gulden PH, Woods AS, Thomas MC, Tong CD, Wang W, et al. The immunodominant major histocompatibility complex class I-restricted antigen of a murine colon tumor derives from an endogenous retroviral gene product. Proc Natl Acad Sci U S A. 1996;93(18):9730–5.CrossRefPubMedPubMedCentral
33.
Simson L, Ellyard JI, Dent LA, Matthaei KI, Rothenberg ME, Foster PS, et al. Regulation of carcinogenesis by IL-5 and CCL11: a potential role for eosinophils in tumor immune surveillance. J Immunol. 2007;178(7):4222–9.CrossRefPubMed
34.
Cormier SA, Taranova AG, Bedient C, Nguyen T, Protheroe C, Pero R, et al. Pivotal Advance: eosinophil infiltration of solid tumors is an early and persistent inflammatory host response. J Leukoc Biol. 2006;79(6):1131–9.CrossRefPubMedPubMedCentral
35.
Carretero R, Sektioglu IM, Garbi N, Salgado OC, Beckhove P, Hammerling GJ. Eosinophils orchestrate cancer rejection by normalizing tumor vessels and enhancing infiltration of CD8(+) T cells. Nat Immunol. 2015;16(6):609–17.CrossRefPubMed
36.
Meggyeshazi N, Andocs G, Balogh L, Balla P, Kiszner G, Teleki I, et al. DNA fragmentation and caspase-independent programmed cell death by modulated electrohyperthermia. Strahlenther Onkol. 2014;1–8.
37.
Feng H, Zeng Y, Graner MW, Katsanis E. Stressed apoptotic tumor cells stimulate dendritic cells and induce specific cytotoxic T cells. Blood. 2002;100(12):4108–15.CrossRefPubMed
38.
Jaffe ML, Arai H, Nabel GJ. Mechanisms of tumor-induced immunosuppression: evidence for contact-dependent T cell suppression by monocytes. Mol Med. 1996;2(6):692–701.PubMedPubMedCentral
39.
Brusa D, Migliore E, Garetto S, Simone M, Matera L. Immunogenicity of 56 degree C and UVC-treated prostate cancer is associated with release of HSP70 and HMGB1 from necrotic cells. Prostate. 2009;69(12):1343–52.CrossRefPubMed
40.
Gallucci S, Lolkema M, Matzinger P. Natural adjuvants: Endogenous activators of dendritic cells. Nat Med. 1999;5(11):1249–55.CrossRefPubMed
41.
Lutz MB, Kukutsch N, Ogilvie AL, Rossner S, Koch F, Romani N, et al. An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J Immunol Methods. 1999;223(1):77–92.CrossRefPubMed
42.
Candido KA, Shimizu K, McLaughlin JC, Kunkel R, Fuller JA, Redman BG, et al. Local administration of dendritic cells inhibits established breast tumor growth: implications for apoptosis-inducing agents. Cancer Res. 2001;61(1):228–36.PubMed
43.
Nosho K, Baba Y, Tanaka N, Shima K, Hayashi M, Meyerhardt JA, et al. Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. J Pathol. 2010;222(4):350–66.CrossRefPubMedPubMedCentral
44.
Benencia F, Sprague L, McGinty J, Pate M, Muccioli M. Dendritic cells the tumor microenvironment and the challenges for an effective antitumor vaccination. J Biomed Biotechnol. 2012;2012:425476.CrossRefPubMedPubMedCentral
45.
Harvey RD. Immunologic and Clinical Effects of Targeting PD-1 in Lung Cancer. Clin Pharmacol Ther. 2014;96(2):214–23.CrossRefPubMed
46.
Metadata
Title
Improving immunological tumor microenvironment using electro-hyperthermia followed by dendritic cell immunotherapy
Authors
Yuk-Wah Tsang
Cheng-Chung Huang
Kai-Lin Yang
Mau-Shin Chi
Hsin-Chien Chiang
Yu-Shan Wang
Gabor Andocs
Andras Szasz
Wen-Tyng Li
Kwan-Hwa Chi
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-015-1690-2

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