Abstract
Recent studies increasingly point to a pivotal role of CD4(+) T cells in human anti-tumor immune response. Here we show that lymphocytes purified from a tumor-infiltrated lymph node of a melanoma patient that had remained disease free for 10 years after surgical resection of a lymph node metastasis comprised oligoclonal class II HLA-restricted CD4(+) T cells recognizing the autologous tumor cells in vitro. In fact, the CD4(+) T cell clones isolated from these lymphocytes displayed a tumor-specific, cytotoxic activity in addition to a Th1-like cytokine profile. By a genetic approach, a peptide derived from a mutated receptor-like protein tyrosine phosphatase kappa was identified as a novel HLA-DR10-restricted epitope for all the melanoma-specific CD4(+) T cell clones. The immunogenic peptide was shown to contain the mutated residue that was crucial for T cell recognition and activation. Moreover, a systemic immunity against the mutated peptide was detectable in the patient's peripheral blood T lymphocytes obtained during the disease-free period of follow-up. These findings further support the relevance of CD4(+) T cells directed against mutated epitopes in tumor immunity and provide the rationale for a possible usage of mutated, tumor-specific Ags for immunotherapy of human cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Antigen Presentation / genetics
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Antigens, Differentiation, B-Lymphocyte / immunology
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Antigens, Differentiation, B-Lymphocyte / metabolism
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Antigens, Neoplasm / biosynthesis
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Antigens, Neoplasm / genetics*
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Antigens, Neoplasm / immunology
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Antigens, Neoplasm / isolation & purification*
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / pathology
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Cell Line, Transformed
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Clone Cells
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Epitopes, T-Lymphocyte / genetics
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Epitopes, T-Lymphocyte / immunology
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Epitopes, T-Lymphocyte / metabolism
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HLA-DR Antigens / immunology*
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HLA-DR Antigens / metabolism
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Histocompatibility Antigens Class II / immunology
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Histocompatibility Antigens Class II / metabolism
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Humans
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Lymphocytes, Tumor-Infiltrating / immunology
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Lymphocytes, Tumor-Infiltrating / pathology
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Melanoma / genetics*
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Melanoma / immunology*
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Melanoma / pathology
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Molecular Sequence Data
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Mutation*
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Peptide Fragments / immunology
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Peptide Fragments / metabolism
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Protein Tyrosine Phosphatases / biosynthesis
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Protein Tyrosine Phosphatases / genetics*
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Protein Tyrosine Phosphatases / immunology
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Protein Tyrosine Phosphatases / isolation & purification*
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RNA, Messenger / biosynthesis
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Receptor-Like Protein Tyrosine Phosphatases, Class 2
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Transfection
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Tumor Cells, Cultured
Substances
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Antigens, Differentiation, B-Lymphocyte
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Antigens, Neoplasm
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Epitopes, T-Lymphocyte
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HLA-DR Antigens
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Histocompatibility Antigens Class II
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Peptide Fragments
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RNA, Messenger
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invariant chain
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PTPRK protein, human
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Protein Tyrosine Phosphatases
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Receptor-Like Protein Tyrosine Phosphatases, Class 2