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Tumor destruction using electrochemotherapy followed by CpG oligodeoxynucleotide injection induces distant tumor responses

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Purpose

Electrochemotherapy (ECT) is an effective local therapy of human cutaneous cancers but has no effect on distant untreated tumors. We addressed whether tumor-associated antigens released after ECT could induce an efficient systemic immunity when associated with an appropriate immunoadjuvant.

Methods and results

We first studied the nature of the cellular recruitment and the expression of various toll-like receptors (TLRs) in tumors treated by ECT. We found that ECT induced a massive recruitment of CD11c and CD11b positive cells in the tumors and a strong increase of TLR9 expression. We then tested antitumor effects of the combination: ECT followed by TLR-9 ligands, CpG oligodeoxynucleotides (CpG ODN), in three murine tumor models. We found that this combination triggered both potent local synergistic antitumor effects, on the ipsi-lateral ECT-treated tumor, and more interestingly, a systemic antitumor response on the contra-lateral untreated tumor, in the three models. The systemic protection was T-cell dependent as it was not observed in nude littermates. The combination induced tumor-specific T cell effectors in the tumor-draining lymph nodes and in the spleen which secreted significantly more gamma-interferon upon activation than with ECT or CpG ODN alone.

Conclusions

Our data show that ECT and CpG ODN synergize and induce a significant increase of the local effect and a systemic T-dependent antitumor response. Such combination constitutes a potential innovative vaccination strategy using in situ tumor-associated antigens that could eventually be translated into the clinic.

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Acknowledgments

We acknowledge Véronique Scott and Stéphanie Esselin for their technical assistance in the development of RT-PCRs and Elisabeth Connault for excellent technical assistance with immunohistochemistry. Grant support CNRS and Institut Gustave Roussy. Stéphan Roux was supported by Fondation pour la Recherche Médicale.

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Authors and Affiliations

  1. INSERM U805, Villejuif, France

    Stephan Roux, François Ghiringhelli & Laurence Zitvogel

  2. CNRS UMR 8121, Villejuif, France

    Claire Bernat, Bassim Al-Sakere, Paule Opolon & Lluis M. Mir

  3. Université Paris-Sud, UMR 8121, Villejuif, France

    Claire Bernat, Bassim Al-Sakere, Paule Opolon & Lluis M. Mir

  4. Service de neurologie, Hôpital Avicenne, Bobigny, France

    Antoine F. Carpentier

  5. UFR de Santé Médecine et Biologie Humaine, Université Paris 13, Bobigny, France

    Antoine F. Carpentier

  6. Département de Médecine, Institut Gustave Roussy, Unité de Dermatologie, 39 rue Camille Desmoulins, 94805, Villejuif Cedex, France

    Caroline Robert

  7. Institut Gustave Roussy, Villejuif, France

    Stephan Roux, Claire Bernat, Bassim Al-Sakere, François Ghiringhelli, Paule Opolon, Laurence Zitvogel, Lluis M. Mir & Caroline Robert

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  1. Stephan Roux
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  2. Claire Bernat
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  3. Bassim Al-Sakere
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  9. Caroline Robert
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Correspondence to Caroline Robert.

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Roux, S., Bernat, C., Al-Sakere, B. et al. Tumor destruction using electrochemotherapy followed by CpG oligodeoxynucleotide injection induces distant tumor responses. Cancer Immunol Immunother 57, 1291–1300 (2008). https://doi.org/10.1007/s00262-008-0462-0

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  • DOI: https://doi.org/10.1007/s00262-008-0462-0

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