Augmentation of immune response by an analog of the antigenic peptide in a human T-cell clone recognizing mutated Ras-derived peptides
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H Yokomizo1, S Matsushita, S Fujisao
1Department of Neuroscience and Immunology, Kumamoto University Graduate School of Medical Sciences, Japan.
Abstract:
T-cells that recognize mutated p21 Ras are relevant to immune surveillance systems against cancer. We report here evidence that immune responses of a T-cell clone recognizing mutated p21 Ras can be augmented by an analog peptide. Using spleen cells from a gastric cancer patient, we established the CD4+ alpha beta Th1-like clone C27 that recognizes wild-type (3EYKLVVVGAGGVGKS17) and mutated p21 Ras protein molecules and peptides, in an HLA-DR1-restricted manner. C27 responded prominently to mutated Ras peptides carrying Val or Ala at position 12, as compared to wild-type and other mutated peptides. C27 also exhibited a much stronger response to a mutated p21 Ras whole-protein molecule-carrying Val at position 12, as compared with the wild-type protein. The proliferative response and production of GM-CSF, TNF-alpha, and IFN-gamma by C27 were further augmented by replacing the possible first DR anchor 4Tyr of the mutated Ras peptide with Trp, a more potent anchor residue for the DR1 molecule. Enhancement of peptide antigenicity by substituting the HLA anchor residue of an antigenic peptide recognized by tumor-reactive T-cells may prove to be a novel strategy for antigen-specific cancer immunotherapy.
Insights
Immune responses against cancer can be boosted by targeting mutated p21 Ras. Modifying a specific peptide enhanced T-cell recognition and activity, offering a new cancer immunotherapy strategy.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- T-cells are crucial for immune surveillance against cancer, particularly those recognizing mutated proteins like p21 Ras.
- Identifying and enhancing T-cell responses to tumor-specific antigens is a key goal in cancer immunotherapy.
Purpose of the Study:
- To establish and characterize a T-cell clone recognizing mutated p21 Ras.
- To investigate methods for augmenting T-cell responses to mutated p21 Ras peptides.
- To explore novel strategies for antigen-specific cancer immunotherapy.
Main Methods:
- Established a CD4+ alpha beta Th1-like T-cell clone (C27) from a gastric cancer patient's spleen cells.
- Assessed T-cell clone C27's recognition of wild-type and mutated p21 Ras proteins and peptides in an HLA-DR1-restricted manner.
- Modified mutated Ras peptides by substituting anchor residues to enhance T-cell proliferation and cytokine production.
Main Results:
- The T-cell clone C27 recognized both wild-type and mutated p21 Ras.
- C27 showed a stronger response to mutated Ras peptides with Val or Ala at position 12 and to the corresponding whole-protein molecule.
- Replacing a tyrosine (Tyr) anchor residue with tryptophan (Trp) in the mutated Ras peptide significantly augmented C27's proliferative response and cytokine production (GM-CSF, TNF-alpha, IFN-gamma).
Conclusions:
- T-cell responses to mutated p21 Ras can be specifically enhanced using analog peptides.
- Substitution of HLA anchor residues in antigenic peptides is a viable strategy to improve T-cell recognition and activation.
- This approach holds promise as a novel method for developing antigen-specific cancer immunotherapies.