Identification of C-met oncogene as a broadly expressed tumor-associated antigen recognized by cytotoxic
Kerstin Schag1, Susanne M Schmidt, Martin R Müller
1Department of Hematology, Oncology and Immunology, University of Tübingen, Tübingen, Germany.
Purpose:
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.
Experimental Design:
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.
Conclusion:
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.
Insights
The c-Met oncogene is identified as a novel tumor rejection antigen. Specific cytotoxic T lymphocytes (CTLs) targeting c-Met effectively lysed various cancer cells, including plasma cells, while sparing healthy cells.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- C-Met proto-oncogene is a receptor tyrosine kinase involved in cancer cell growth.
- Hepatocyte growth factor signaling through C-Met drives oncogenic activities.
- A novel peptide derived from c-Met was recently identified in renal cell carcinoma.
Purpose of the Study:
- To investigate the potential of a c-Met-derived peptide for inducing specific cytotoxic T lymphocytes (CTLs).
- To analyze the presentation of this c-Met epitope by malignant cells.
- To evaluate the efficacy of c-Met-specific CTLs against various cancer types.
Main Methods:
- DNA chip analysis and peptide sequencing identified a c-Met-derived peptide.
- Induction of CTLs using the identified HLA-A*0201 peptide.
- Assays to assess antigen-specific and HLA-restricted lysis of target cells.
- Recognition studies using autologous dendritic cells (DCs) and tumor mRNA.
- Induction of c-Met-specific CTLs from a patient with plasma cell leukemia.
Main Results:
- Induced CTLs efficiently lysed peptide-pulsed target cells and HLA-A*0201-matched tumor cell lines.
- c-Met-specific CTLs recognized peptide-pulsed DCs and DCs transfected with c-Met-expressing tumor mRNA.
- CTLs generated from a plasma cell leukemia patient lysed autologous malignant plasma cells.
- These CTLs demonstrated specificity, sparing non-malignant lymphocytes and other immune cells.
Conclusions:
- The c-Met oncogene serves as a novel tumor rejection antigen.
- c-Met is recognized by CTLs in an antigen-specific and HLA-restricted manner.
- This antigen is expressed on a wide range of epithelial and hematopoietic malignancies, indicating broad therapeutic potential.
