Identification of C-met oncogene as a broadly expressed tumor-associated antigen recognized by cytotoxic T-lymphocytes.
OBJECTIVE
C-Met proto-oncogene is a receptor tyrosine kinase that mediates the oncogenic activities of the hepatocyte growth factor. Using a DNA chip analysis of tumor samples from patients with renal cell carcinoma and sequencing of peptides bound to the HLA-A*0201 molecules on tumor cells a peptide derived from the c-Met protein was identified recently.


METHODS
We used this novel HLA-A*0201 peptide for the induction of specific CTLs to analyze the presentation of this epitope by malignant cells.


RESULTS
The induced CTL efficiently lysed target cells pulsed with the cognate peptide, as well as HLA-A*0201-matched tumor cell lines in an antigen-specific and HLA-restricted manner. Furthermore, the induced c-Met-specific CTLs recognized autologous dendritic cells (DCs) pulsed with the peptide or transfected with whole-tumor mRNA purified from c-Met-expressing cell lines. We next induced c-Met-specific CTLs using peripheral blood mononuclear cells and DC from an HLA-A*0201-positive patient with plasma cell leukemia to determine the recognition of primary autologous malignant cells. These CTLs lysed malignant plasma cells while sparing nonmalignant B- and T-lymphocytes, monocytes, and DCs.


CONCLUSIONS
Our results demonstrate that c-Met oncogene is a novel tumor rejection antigen recognized by CTL and expressed on a broad variety of epithelial and hematopoietic malignant cells.
Schag
Kerstin
K
Department of Hematology, Oncology and Immunology, University of Tübingen, Tübingen, Germany.
Schmidt
Susanne M
SM
Müller
Martin R
MR
Weinschenk
Toni
T
Appel
Silke
S
Weck
Markus M
MM
Grünebach
Frank
F
Stevanovic
Stefan
S
Rammensee
Hans-Georg
HG
Brossart
Peter
P
D000941:Antigens / Q000737:chemistry; D000951:Antigens, Neoplasm / Q000737:chemistry*; D001402:B-Lymphocytes / Q000378:metabolism; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000166:cytology; D004591:Electrophoresis, Polyacrylamide Gel; D018274:Electroporation; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000737:chemistry; D015234:HLA-A Antigens / Q000096:biosynthesis / Q000235:genetics; D015789:HLA-A2 Antigen; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010455:Peptides / Q000737:chemistry; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis* / Q000235:genetics*; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism*; D013997:Time Factors
D000941:Antigens; D000951:Antigens, Neoplasm; D000939:Epitopes; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; C000715470:MAS1 protein, human; D010455:Peptides; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D012313:RNA; D007371:Interferon-gamma; D019859:Proto-Oncogene Proteins c-met