Identification of cytotoxic T-lymphocyte epitope(s) and its agonist epitope(s) of a novel target for vaccine therapy (PAGE4).
PAGE4 is an X chromosome-linked cancer testis antigen and is a potential new tumor-associated antigen that is overexpressed in prostate and uterine cancers. The purpose of this study was to identify a human CTL epitope and a corresponding agonist epitope of PAGE4 to determine if PAGE4 is a potential target for vaccine-mediated immunotherapy against PAGE4-expressing tumors. A class I PAGE4 epitope was identified with a high level of binding to HLA-A2. PAGE4 peptide-pulsed dendritic cells were then used to generate human PAGE4-specific T-cell lines. Further studies demonstrated the generation of an enhancer agonist epitope. Compared with the native peptide, the agonist (i) bound to HLA-A2 molecules at lower peptide concentrations, (ii) demonstrated a higher stability of the peptide HLA-A2 complex, (iii) induced higher levels of production of IFN-gamma, Granzyme B, TNF-alpha, IL-2 and lymphotactin by PAGE4-specific T-cell lines and (iv) T-cell lines generated against the agonist peptide were more efficient to lyse HLA-A2 human tumor cells expressing native PAGE4. The studies reported here are the first to describe a PAGE4 CTL epitope and its agonist epitope, and thus identify PAGE4 as a potentially useful target for vaccine-mediated therapy of prostate cancer.
Yokokawa
Junko
J
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD.
Bera
Tapan K
TK
Palena
Claudia
C
Cereda
Vittore
V
Remondo
Cinzia
C
Gulley
James L
JL
Arlen
Philip M
PM
Pastan
Ira
I
Schlom
Jeffrey
J
Tsang
Kwong Y
KY
D000951:Antigens, Neoplasm / Q000737:chemistry*; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000502:physiology; D000939:Epitopes / Q000032:analysis*; D018984:Epitopes, T-Lymphocyte / Q000032:analysis*; D015789:HLA-A2 Antigen / Q000737:chemistry; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000737:chemistry*; D013602:T-Lymphocytes, Cytotoxic / Q000737:chemistry*; D014162:Transfection
D000951:Antigens, Neoplasm; D000939:Epitopes; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; C474505:PAGE4 protein, human