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T cell recognition of transforming proteins encoded by mutated ras proto-oncogenes
Abstract:
Activated ras proto-oncogenes contribute to the pathogenesis of many animal and human malignancies. ras proto-oncogenes are generally activated by point mutations within codons 12 or 61, which result in the expression of ras protein (p21) bearing characteristic single amino acid substitutions at the corresponding residues. The purpose of the current study was to determine whether the presence of single transforming amino acid substitutions can render normal ras protein immunogenic and, thus, a possible target for T cell-mediated tumor therapy. In initial experiments, C57BL/6 mice were immunized with a synthetic peptide corresponding to residues 5 through 16 of p21 containing the transforming substitution of arginine for normal glycine at residue 12. The results demonstrated that class II MHC-restricted T cells which were specific for the peptide could be elicited, and that the peptide-induced T cells could specifically recognize the corresponding intact p21 ras protein. Recognition of p21 ras protein by peptide-specific T cells implies that C57BL/6 APC can process the activated ras protein in a fashion that allows presentation of digested protein by class II MHC molecules in a configuration similar to the configuration with synthetic peptide. Evaluation of the immunogenicity of peptides containing alternative transforming amino acid substitutions of ras protein demonstrated that some, but not all, were immunogenic in individual strains of mice. Therefore, although ras protein-specific T cells can be elicited by immunization with synthetic peptides, not all of the potential ras mutations commonly associated with malignancy may be recognizable by T cells from all individuals.
Insights
This study shows that specific ras protein mutations can be recognized by T cells, suggesting potential for T cell-mediated tumor therapy. However, not all ras mutations are immunogenic, limiting broad applicability.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Activated ras proto-oncogenes are implicated in numerous malignancies.
- Ras protein activation typically involves point mutations at codons 12 or 61, leading to amino acid substitutions.
Purpose of the Study:
- To investigate if single transforming amino acid substitutions in ras protein can make it immunogenic.
- To explore the potential of ras protein as a target for T cell-mediated tumor therapy.
Main Methods:
- Immunization of C57BL/6 mice with a synthetic peptide containing a specific ras mutation (Gly12Arg).
- Assessment of T cell responses to the peptide and the intact ras protein.
- Evaluation of the immunogenicity of peptides with alternative ras mutations.
Main Results:
- Class II MHC-restricted T cells specific for the mutated peptide were elicited.
- These T cells recognized the intact p21 ras protein, indicating antigen processing and presentation by APCs.
- Some, but not all, alternative ras mutation peptides were immunogenic in different mouse strains.
Conclusions:
- Ras protein-specific T cells can be generated through immunization with synthetic peptides.
- The immunogenicity of ras mutations varies, suggesting that not all cancer-associated ras mutations may be targets for T cell therapy in all individuals.