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CpG-Oligodeoxynucleotides activate tyrosinase-related protein 2–specific T lymphocytes but do not lead to a protective tumor-specific memory response

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Abstract

Purpose: Peritumoral CpG-oligodeoxynucleotide (ODN) treatment has been successful in tumor mouse models expressing strong antigens to induce activation of tumor-specific CD8+ T lymphocytes which contribute to the control of tumor growth. To get near to clinical reality, the tumor-specific CD8+ response was investigated in mice bearing the weakly immunogenic B16 melanoma tumor and using the melanocyte differentiation tyrosinase-related protein 2 (TRP-2) as a tracking antigen. Methods: The expansion and activation of TRP-2–specific T lymphocytes by CpG-ODNs was analyzed by tetramer staining and IFN-γ production assays, while the activity of these cells in both memory and primary response was evaluated in vivo. Results: After CpG-ODN treatment, the number of TRP-2 tetramer-stained CD8+ T lymphocytes was not significantly modified, but these cells produced higher levels of interferon γ (IFN-γ) in response to the antigen than those from untreated mice. Mice possessing these activated T lymphocytes, when evaluated for their antitumor memory response, showed marginal protection against intravenous (i.v.) and subcutaneous (s.c.) tumor rechallenge. These cells were not crucial for the control of primary tumor growth since strong reduction of subcutaneous tumor was observed after CpG-ODN treatment in both CD8+ T cell depleted or nondepleted mice. On the contrary, NK cell depletion markedly reduced CpG-ODN-induced tumor growth inhibition. Conclusions: Altogether, these data indicate the CpG treatment activates tumor-reactive effector CD8+ T lymphocytes, but, paralleling recent clinical observations, our model indicates that the mere activation of antitumor T cells is insufficient to result in a clinical response.

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Abbreviations

CpG:

unmethylated CpG dinucleotides

ODNs:

oligodeoxynucleotides

TLR9:

toll-like receptor 9

TRP-2:

tyrosinase-related protein 2

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Acknowledgements

Supported by AIRC and FIRST. L.S. was supported by a fellowship from FIRC. We thank Dr Thomas Tuting for kindly providing the hTRP-2–encoding recombinant adenovirus.

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Authors and Affiliations

  1. Molecular Targeting Unit, Department of Experimental Oncology, Istituto Nazionale Tumori, Via Venezian 1, 20133, Milan, Italy

    Lucia Sfondrini, Dario Besusso, Anna Rossini, Sylvie Ménard & Andrea Balsari

  2. Immunotherapy and Gene Therapy Unit, Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy

    Mario Paolo Colombo

  3. Department of Oncology and Surgical Sciences, Oncology Section, Azienda Ospedaliera, Padova, Italy

    Vincenzo Bronte & Beatrice Macino

  4. Institute of Pathology, University of Milan, Milan, Italy

    Andrea Balsari

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  1. Lucia Sfondrini
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Correspondence to Andrea Balsari.

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Sfondrini, L., Besusso, D., Bronte, V. et al. CpG-Oligodeoxynucleotides activate tyrosinase-related protein 2–specific T lymphocytes but do not lead to a protective tumor-specific memory response. Cancer Immunol Immunother 53, 697–704 (2004). https://doi.org/10.1007/s00262-004-0516-x

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