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Peptide-based, but not whole protein, vaccines elicit immunity to HER-2/neu, oncogenic self-protein
M L Disis1, J R Gralow, H Bernhard
1Department of Medicine, University of Washington, Seattle 98195, USA.
Abstract:
HER-2/neu, an overexpressed oncogenic protein, has been proposed as a human cancer vaccine target. HER-2/neu is a "self" protein, however, and methods of vaccine strategies that would be effective in immunizing patients to a "self" tumor Ag have not been established. Many of the tumor Ags defined in humans are nonmutated self proteins, e.g., MAGE, and overcoming tolerance may be key in the generation of effective anti-tumor immunity. One theory states that tolerance to self proteins is directed only to dominant epitopes of proteins and not to every portion of the protein. Accordingly, tolerance can be circumvented by immunization to peptide fragments, but not whole protein. The studies outlined here demonstrate rat neu-specific immunity could be elicited in rats by vaccination with immunogenic rat neu peptides, but not by immunization with the intact protein. A rat model was used since rat neu protein is 89% homologous to human HER-2/neu protein and has a similar tissue distribution and level of expression. Rats were immunized with groups of peptides derived from the amino acid sequence of the intracellular domain or extracellular domain of rat neu protein and both groups developed CD4+ T cell immunity and Ab immunity to rat neu peptides and protein. Animals immunized in a similar fashion with intact purified rat neu protein did not develop Ab or T cell immunity to rat neu. Furthermore, rats that developed neu-specific immunity showed no histopathologic evidence of autoimmunity directed against organs expressing basal levels of rat neu protein. These studies suggest an immunization strategy that might be effective in human cancer vaccines targeting self tumor Ag.
Insights
Vaccinating with specific peptide fragments of the HER-2/neu protein, a self tumor antigen, successfully generated immunity in rats. Immunization with the whole protein did not induce immunity, suggesting a novel cancer vaccine strategy.
Area of Science:
- Oncology
- Immunology
- Vaccine Development
Background:
- HER-2/neu is an overexpressed oncogenic protein and a potential target for human cancer vaccines.
- Effective immunization against
- self
- tumor antigens like HER-2/neu is challenging due to established immune tolerance.
- Overcoming self-tolerance is crucial for generating anti-tumor immunity.
Purpose of the Study:
- To investigate if immunization with specific peptide fragments of the rat neu protein (homologous to human HER-2/neu) can elicit an immune response.
- To evaluate the efficacy of targeting self tumor antigens by circumventing immune tolerance.
Main Methods:
- Rats were immunized with peptide fragments derived from the intracellular or extracellular domains of rat neu protein.
- Control groups were immunized with intact purified rat neu protein.
- Immune responses, including CD4+ T cell immunity and antibody (Ab) immunity, were assessed.
- Autoimmunity was evaluated by examining organs expressing basal levels of rat neu protein.
Main Results:
- Rats immunized with rat neu peptides developed both CD4+ T cell immunity and Ab immunity to rat neu peptides and protein.
- Rats immunized with intact rat neu protein did not develop T cell or Ab immunity.
- No histopathologic evidence of autoimmunity was observed in rats that developed neu-specific immunity.
Conclusions:
- Immunization with immunogenic peptides derived from self tumor antigens, like HER-2/neu, can successfully elicit specific immunity.
- This peptide-based immunization strategy circumvents tolerance to self proteins without inducing autoimmunity.
- These findings suggest a promising approach for developing human cancer vaccines targeting self tumor antigens.