Fine analysis of spontaneous MAGE-C1/CT7-specific immunity in melanoma patients.
Cancer/testis (CT) antigens represent prime candidates for immunotherapy in cancer patients, because their expression is restricted to cancer cells and germ cells of the testis. MAGE-C1/CT7 is a CT antigen that is highly expressed in several types of cancers. Spontaneous occurrence of CT7-specific antibodies was previously detected by SEREX screen in a melanoma patient. However, naturally occurring CT7-specific T-cell responses have thus far not been detected. Peripheral blood mononuclear cells (PBMCs) from 26 metastatic melanoma patients expressing CT7 in their tumor lesions (CT7(+)) were analyzed for CT7-specific T-cell responses using overlapping peptides. CT7-specific CD4(+) T-cell responses were detected in three patients (11.5%). These CT7-specific CD4(+) T-cell responses were detectable in melanoma patients' PBMCs exclusively from preexisting CD45RA(-) memory CD4(+) T-cell pool. Additional CT7-specific memory CD4(+) T-cell responses were detected in CT7(+) melanoma patients after depletion of CD4(+)CD25high Treg cells showing that Treg cells impact on CT7-specific CD4(+) T cells in melanoma patients. CT7-specific CD4(+) T-cell clones were generated and used to define minimal epitopes, restriction elements, and confirm the recognition of naturally processed antigen. Surprisingly, these clones were able to secrete perforin and exert cytotoxicity. This study shows that CT7 can induce specific cellular immunity in melanoma patients. Based on these findings, CT7 will be further explored as a potential vaccine for melanoma immunotherapy.
Nuber
Natko
N
Department of Oncology, University Hospital Zurich, CH-8091 Zurich, Switzerland.
Curioni-Fontecedro
Alessandra
A
Matter
Claudia
C
Soldini
Davide
D
Tiercy
Jean Marie
JM
von Boehmer
Lotta
L
Moch
Holger
H
Dummer
Reinhard
R
Knuth
Alexander
A
van den Broek
Maries
M
D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology; D045744:Cell Line, Tumor; D018604:Epitope Mapping; D000939:Epitopes / Q000235:genetics; D006801:Humans; D007156:Immunologic Memory; D066298:In Vitro Techniques; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000556:secondary / Q000628:therapy; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D000951:Antigens, Neoplasm; C473332:CT7 antigen, human; D019496:Cancer Vaccines; D000939:Epitopes; C110905:MAGEC1 protein, human; D009363:Neoplasm Proteins