Identification of an HLA-DR-restricted peptide epitope with a promiscuous binding pattern derived from the cancer testis antigen HOM-MEL-40/SSX2.
The SSX2 gene encodes the tumor-specific antigen HOM-MEL-40/SSX2 expressed in a broad spectrum of tumors of different origin, against which humoral and CD8+ T-cell-mediated MHC-I-restricted responses have been demonstrated. Searching for promiscuous MHC-II-restricted peptides that might be suitable as a CD4+ stimulating vaccine for many patients, we used the SYFPEITHI algorithm and identified a HOM-MEL-40/SSX2-derived pentadecamer epitope (p45-59) that induced specific CD4+ T-cell responses restricted by the HLA-DRB1 subtypes *0701, *1101 and *1302 that have a cumulative prevalence of approximately 25% in the Caucasian population. The CD4+-mediated response against p45-59 and its DR restriction was demonstrated by inhibition with anti-CD4 and HLA-DR antibodies, respectively, and by blocking experiments using HLA-specific antibodies. The natural processing and presentation of p45-59 was demonstrated by recognition of the SSX2+ melanoma cell line Me 275 as well as autologous and allogeneic dendritic cells pulsed with whole-protein SSX2 by T cells with specificity for p45-59. p45-59 was able to induce responses in 3/6 breast cancer patients and 1/5 healthy controls. No correlation was found between CD4+ T-cell responses against p45-59 reactivity and anti-SSX2 antibody titers in the serum of patients, suggesting that CD4+ and B-cell responses are regulated independently. p45-59 holds promise as a broadly applicable peptide vaccine for patients with SSX2-positive neoplasms.
Neumann
Frank
F
Medizinische Klinik I, Saarland University Medical School, Homburg, Germany.
Wagner
Claudia
C
Stevanovic
Stefan
S
Kubuschok
Boris
B
Schormann
Claudia
C
Mischo
Axel
A
Ertan
Kubilay
K
Schmidt
Werner
W
Pfreundschuh
Michael
M
D000917:Antibody Formation; D000951:Antigens, Neoplasm / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D001943:Breast Neoplasms / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology*; D003713:Dendritic Cells; D000939:Epitopes; D005260:Female; D006684:HLA-DR Antigens / Q000235:genetics*; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D000939:Epitopes; D006684:HLA-DR Antigens; D009363:Neoplasm Proteins; D012097:Repressor Proteins; C093962:synovial sarcoma X breakpoint proteins