Proliferative and cytokine responses to class II HER-2/neu-associated peptides in breast cancer patients.
Previous studies have characterized the reactivity of CD8+ CTLs with ovarian and breast cancer. There is little information about the antigens and epitopes recognized by CD4+ T cells in these patients. In this study, we analyzed the ability of T cells from peripheral blood mononuclear cells of breast cancer patients to recognize HER-2/neu (HER-2) peptides. We found that 13 of 18 patients responded by proliferation to at least one of the HER-2 peptides tested. Of these peptides, one designated G89 (HER-2: 777-789) was recognized by T cells from 10 patients. Seven of nine responding patients were HLA-DR4+, suggesting that this peptide is recognized preferentially in association with HLA-DR4. Analysis of the specificity and restriction of the cytokine responses to G89 by G89-stimulated T cells revealed that these cells secreted significantly higher levels of IFN-gamma than interleukin 4 and interleukin 10, suggesting priming for a Th0-T helper 1 response. The same pattern of cytokine responses was observed to the intracellular domain of HER-2 protein, suggesting that G89-stimulated T cells recognized epitopes of the HER-2 protein in association with HLA-DR4. Because HLA-DR4 is present in 25% of humans, characterization of MHC class II-restricted epitopes inducing Th0-T helper 1 responses may provide a basis for the development of multivalent HER-2-based vaccines against breast and ovarian cancer.
Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
T M
TM
Tuttle
B W
BW
Anderson
W E
WE
Thompson
J E
JE
Lee
A
A
Sahin
T L
TL
Smith
K H
KH
Grabstein
J T
JT
Wharton
C G
CG
Ioannides
J L
JL
Murray
D000595:Amino Acid Sequence; D001943:Breast Neoplasms / Q000097:blood* / Q000276:immunology / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis* / Q000378:metabolism*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000494:pharmacology*; D017386:Sequence Homology, Amino Acid; D013268:Stimulation, Chemical; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism
D016207:Cytokines; D007371:Interferon-gamma; D010446:Peptide Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases