Specific human cellular immunity to bcr-abl oncogene-derived peptides.
Chronic myelogenous leukemia (CML) cells are characterized by a t(9;22) translocation, which can encode one of two chimeric P210 bcr-abl fusion proteins, comprising products of either the b2a2 or the b3a2 exon junction. The junctional sequences represent potentially immunogenic tumor-specific antigens. Despite their intracellular location, the fusion proteins might be recognized immunologically by T lymphocytes if peptides, derived from these unique sequences, are capable of presentation by the major histocompatibility complex molecules. We previously found that four peptides, 9 to 11 amino acids long, spanning the b3a2 CML breakpoint bind with high or intermediate affinity to purified HLA class I molecules A3, A11, B8, or both A3 and A11. We tested the ability of these peptides to elicit specific class I restricted cytotoxic T lymphocytes (CTLs) in vitro in HLA-matched healthy donors. In addition, a longer b3a2 CML-breakpoint-derived peptide, 25 aminoacids in length (b3a2-25), was studied for its ability to induce peptide-specific, class II-mediated, T-cell proliferation. In four of four HLA-A3 donors tested, CML-A3/A11-peptide specific CTLs were induced that killed an allogeneic HLA-A3-matched peptide pulsed leukemia cell line. In two of three HLA-A3 donors, the CML-A3/A11 peptide was able to induce killing of autologous and allogeneic HLA-matched peptide-pulsed peripheral blood mononuclear cells (PBMC). CML-A3 peptide induced peptide specific CTLs in one of the four HLA A3 donors tested. No killing was observed in two HLA-B8 and two HLA-A11 donors. PBMC from seven donors were also tested for anti b3a2-25 peptide proliferation in a thymidine incorporation assay. Specific proliferation was detected in three donors, all of the HLA-DR11 haplotype. These data represent the first evidence of a cytolytic human immune response against CML bcr-abl oncogene-derived peptides and provide a rationale for developing peptide-based vaccines for this disease.
Bocchia
M
M
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York 10021, USA.
Korontsvit
T
T
Xu
Q
Q
Mackinnon
S
S
Yang
S Y
SY
Sette
A
A
Scheinberg
D A
DA
D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular; D008213:Lymphocyte Activation / Q000276:immunology; D008969:Molecular Sequence Data; D015513:Oncogene Proteins / Q000276:immunology*; D010455:Peptides / Q000138:chemical synthesis / Q000276:immunology; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D016315:Proto-Oncogene Proteins c-abl / Q000276:immunology*; D051562:Proto-Oncogene Proteins c-bcr; D011993:Recombinant Fusion Proteins / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000473:pathology; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D015513:Oncogene Proteins; D010455:Peptides; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr