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TLR9 agonist enhances radiofrequency ablation-induced CTL responses, leading to the potent inhibition of primary tumor growth and lung metastasis 

Cellular & Molecular Immunology volume 16, pages 820–832 (2019)Cite this article

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Abstract

Radiofrequency ablation (RFA) is the most common approach to thermal ablation for cancer therapy. Unfortunately, its efficacy is limited by incomplete ablation, and further optimization of RFA is required. Here, we demonstrate that incubation at 65 °C triggers more EG7 tumor cell death by necrosis than treatment at 45 °C, and the 65 °C-treated cells are more effective at inducing antigen-specific CD8+ cytotoxic T lymphocyte (CTL) responses after injection in mice than the 45 °C-treated ones. Dendritic cells (DCs) that phagocytose 65 °C-treated EG7 cells become mature with upregulated MHCII and CD80 expression and are capable of efficiently inducing effector CTLs in mouse tumor models. RFA (65 °C) therapy of EG7 tumors induces large areas of tumor necrosis and stimulates CTL responses. This leads to complete regression of small (~100 mm3) tumors but fails to suppress the growth of larger (~350 mm3) tumors. The administration of the Toll-like receptor-9 (TLR9) agonist unmethylated cytosine-phosphorothioate-guanine oligonucleotide (CpG) to DCs phagocytosing 65 °C-treated EG7 cells enhances the expression of MHCII and CD40 on DCs as well as DC-induced stimulation of CTL responses. Importantly, the intratumoral administration of CpG following RFA also increases the frequencies of tumor-associated immunogenic CD11b−CD11c+CD103+ DC2 and CD11b+F4/80+MHCII+ M1 macrophages and increases CD4+ and CD8+ T-cell tumor infiltration, leading to enhanced CD4+ T cell-dependent CTL responses and potent inhibition of primary RFA-treated or distant untreated tumor growth as well as tumor lung metastasis in mice bearing larger tumors. Overall, our data indicate that CpG administration, which enhances RFA-induced CTL responses and ultimately potentiates the inhibition of primary tumor growth and lung metastasis, is a promising strategy for improving RFA treatment, which may assist in optimizing this important cancer therapy.

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Acknowledgements

This work was supported by grants from CoMRAD (#417578), College of Medicine, University of Saskatchewan, Prostate Cancer Fight Foundation (#417782), Royal University Hospital Research Foundation (#417450) and Saskatchewan Health Research Foundation (#418672).

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Authors and Affiliations

  1. Cancer Research, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, SK, Canada

    Aizhang Xu, Jingying Yuan, Fatma Babikr & Jim Xiang

  2. Department of Oncology, University of Saskatchewan, Saskatoon, SK, Canada

    Aizhang Xu, Jingying Yuan, Fatma Babikr & Jim Xiang

  3. Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China

    Lifeng Zhang

  4. Department of Pathology, University of Saskatchewan, Saskatoon, SK, Canada

    Andrew Freywald & Rajni Chibbar

  5. Department of Surgery, University of Saskatchewan, Saskatoon, SK, Canada

    Michael Moser

  6. Department of Bioengineering, University of Saskatchewan, Saskatoon, SK, Canada

    Wenjun Zhang

  7. Biomedical Science and Technology Research Center, School of Mechatronic Engineering and Automation, Shanghai University, Shanghai, China

    Bing Zhang

  8. Department of Immunology, College of Medicine, Yian-An University, Yian-An, China

    Zhaoying Fu

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  1. Aizhang Xu
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Xu, A., Zhang, L., Yuan, J. et al. TLR9 agonist enhances radiofrequency ablation-induced CTL responses, leading to the potent inhibition of primary tumor growth and lung metastasis . Cell Mol Immunol 16, 820–832 (2019). https://doi.org/10.1038/s41423-018-0184-y

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