Identification of a mutated receptor-like protein tyrosine phosphatase kappa as a novel, class II HLA-restricted melanoma antigen.
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.
Novellino
Luisa
L
Unit of Immunotherapy of Human Tumors and Unit of Molecular Mechanisms of Tumor Growth and Progression, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
Renkvist
Nicolina
N
Rini
Francesca
F
Mazzocchi
Arabella
A
Rivoltini
Licia
L
Greco
Angela
A
Deho
Paola
P
Squarcina
Paola
P
Robbins
Paul F
PF
Parmiani
Giorgio
G
Castelli
Chiara
C
D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000235:genetics; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology / Q000302:isolation & purification*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002461:Cell Line, Transformed; D002999:Clone Cells; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006684:HLA-DR Antigens / Q000276:immunology* / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000473:pathology; D008545:Melanoma / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology / Q000302:isolation & purification*; D012333:RNA, Messenger / Q000096:biosynthesis; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D014162:Transfection; D014407:Tumor Cells, Cultured
D000944:Antigens, Differentiation, B-Lymphocyte; D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments; D012333:RNA, Messenger; C045084:invariant chain; C489852:PTPRK protein, human; D017027:Protein Tyrosine Phosphatases; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2