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Published on: May 27, 2011
CpG-Oligodeoxynucleotides activate tyrosinase-related protein 2-specific T lymphocytes but do not lead to a
Lucia Sfondrini1, Dario Besusso, Vincenzo Bronte
1Molecular Targeting Unit, Department of Experimental Oncology, Istituto Nazionale Tumori, Via Venezian 1, 20133, Milan, Italy.
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-gamma 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 gamma (IFN-gamma) 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.
Insights
CpG-oligodeoxynucleotide (ODN) treatment activates tumor-reactive CD8+ T cells, but this activation alone is insufficient for a clinical response in weakly immunogenic melanoma models. Natural killer (NK) cells play a crucial role in the anti-tumor effect.
Area of Science:
- Immunology
- Cancer Research
- T-cell Therapy
Background:
- Peritumoral CpG-oligodeoxynucleotide (ODN) treatment effectively activates tumor-specific CD8+ T lymphocytes in models with strong antigens.
- Investigating this immune response in weakly immunogenic B16 melanoma models is crucial for clinical translation.
Purpose of the Study:
- To investigate the CD8+ T-cell response to CpG-ODN treatment in a weakly immunogenic B16 melanoma mouse model.
- To evaluate the role of tyrosinase-related protein 2 (TRP-2) as a tracking antigen for melanocyte differentiation.
- To assess the in vivo activity of TRP-2-specific T lymphocytes in primary and memory responses.
Main Methods:
- Analyzed expansion and activation of TRP-2-specific T lymphocytes using tetramer staining and IFN-gamma production assays.
- Evaluated the in vivo activity of these T cells in both memory and primary responses.
- Assessed tumor growth inhibition in CD8+ T cell-depleted and non-depleted mice, and in NK cell-depleted mice.
Main Results:
- CpG-ODN treatment increased IFN-gamma production in TRP-2-specific CD8+ T lymphocytes but did not significantly alter their numbers.
- Activated T lymphocytes provided marginal protection against tumor rechallenge in memory responses.
- CD8+ T cells were not crucial for primary tumor growth control; NK cell depletion markedly reduced CpG-ODN-induced tumor growth inhibition.
Conclusions:
- CpG-ODN treatment activates tumor-reactive effector CD8+ T lymphocytes.
- The mere activation of antitumor T cells is insufficient for a clinical response, aligning with recent clinical observations.
- Natural killer (NK) cells are critical for CpG-ODN-mediated tumor growth inhibition in this model.
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