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Combination of magnetic hyperthermia and immunomodulators to drive complete tumor regression of poorly immunogenic melanoma

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Abstract

Hyperthermia using magnetic nanoparticles enables tumor-specific heating and can destroy tumor tissues. This approach works as in situ vaccination with tumor antigens released from dying tumor cells. However, in situ vaccination caused by magnetic hyperthermia is often insufficient to induce complete regression of poorly immunogenic tumors surrounded by an immunosuppressive microenvironment. In this study, we explored a novel strategy for immunotherapy using magnetic hyperthermia to regress poorly immunogenic melanoma. Magnetic hyperthermia induced tumor cell death in a B16-F10 melanoma mouse model. After hyperthermia treatment, we found elevated levels of HMGB1, which is known to be released from dying cells to promote inflammation, and the proinflammatory cytokine TNF-α was increased in serum of the mice. Systemic administration of glycyrrhizin, an HMGB1 inhibitor, reduced the levels of TNF-α in serum and successfully delayed the regrowth of tumors after magnetic hyperthermia. To achieve complete tumor regression, TLR9 activation by intratumor injection of CpG was combined with systemic administration of anti-PD-1 antibody and anti-CTLA-4 antibody. The combination therapy of magnetic hyperthermia at 46°C with the immunomodulators (glycyrrhizin+CpG+anti-PD-1+anti-CTLA-4) achieved complete tumor regression in 80% of growing 5-mm B16-F10 tumors. These findings have important implications for the development of novel cancer immunotherapy using magnetic hyperthermia for poorly immunogenic tumors.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

αPD1:

Anti-PD-1 antibody

αCTLA4:

Anti-CTLA-4 antibody

AMF:

Alternating magnetic field

CTLA-4:

Cytotoxic T lymphocyte-associated protein-4

DAMP:

Damage-associated molecular pattern

FBS:

Fetal bovine serum

HSP:

Heat shock protein

MCL:

Magnetite cationic liposome

MDSC:

Myeloid-derived suppressor cell

PD-1:

Programmed death-1

PD-L1:

Programed death-ligand 1

pDC:

Plasmacytoid dendritic cell

RAGE:

Receptor for advanced glycation end products

TLR:

Toll-like receptor

TNF-α:

Tumor necrosis factor-α

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Acknowledgements

This work was partially supported by JSPS KAKENHI (Nos. 20H02538 and 19K22086). We thank Gabrielle White Wolf, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Funding

This work was partially supported by JSPS KAKENHI (No. 20H02538 and No. 19K22086).

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Authors and Affiliations

  1. Department of Chemical Systems Engineering, School of Engineering, Nagoya University, Furo-Cho, Chikusa-Ku, Nagoya, 464-8603, Japan

    Ami Nishikawa, Yutaro Suzuki, Masahiro Kaneko & Akira Ito

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  1. Ami Nishikawa
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  2. Yutaro Suzuki
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  3. Masahiro Kaneko
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  4. Akira Ito
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by A.N. and Y.S. The first draft of the manuscript was written by A.I. and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Akira Ito.

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Conflict of interests

The authors declare no competing interests.

Ethics approval and consent to participate

All animal experiments were approved by the Ethics Committee for Animal Experiments of the School of Engineering, Nagoya University (G220006).

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The clinical studies mentioed above paragraph were approved by Clinical Trial Research Protocol No. 18-67, Sapporo Medical University with funding for research on Advanced Medical Technology from the Ministry of Health, Labor and Welfare of Japan [Project No. H21-Nano-6]. In the case of the present paper, the manuscript is approved by all authors for publication.

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Nishikawa, A., Suzuki, Y., Kaneko, M. et al. Combination of magnetic hyperthermia and immunomodulators to drive complete tumor regression of poorly immunogenic melanoma. Cancer Immunol Immunother 72, 1493–1504 (2023). https://doi.org/10.1007/s00262-022-03345-8

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