The immunotherapy of cancer aims to activate both the humoral and cellular arms of the immune system to generate a specific and effective anti-tumor response. Tumor cells express self-antigens which masks these cells from recognition by the immune system. Tumor cells display antigen in the context of Human Leukocyte Antigen (HLA) molecules presented on the cell surface. Cytotoxic T lymphocyte (CTL) recognition of antigenic peptide/HLA complexes results in destruction of the target cell. CTL are educated to discriminate between foreign and self-antigens, however tumor cells frequently express self-antigens, rendering tumors poorly immunogenic. Several tumor-derived peptides have a weak affinity for HLA molecules and are therefore inefficiently presented to T cells. Peptides bind to HLA molecules through anchor residues on both the carboxy and amino termini. Modification of peptides at critical HLA-binding residues can (i) increase the affinity of a peptide for HLA molecules, therefore increasing the opportunity for peptide presentation to tumor-specific T cells and (ii) result in the generation of 'altered self' (altered peptide ligands) with the potential to activate CTL. It was hypothesized that the substitution of preferred HLA-A*0201-binding acids into tumor-derived peptides would increase the binding affinity of the peptides for HLA-A2 molecules (compared to wild type tumor peptide), resulting in activation of CTL specific for wild type tumor peptide. Altered peptide ligands (APL) were rationally designed for two tumor antigens, gp100 and Her-2/neu. Amino acid modifications were introduced into immunodominant, HLA-A*0201-binding nonamer peptides, gp100 (ITDQVPFSV, residues 209--217) and E75 (KIFGSLAFL, residues 369--377). Tumor APL were evaluated for HLA-A*0201 binding affinity and the ability to activate CTL specific for wild type tumor peptide. The work presented here demonstrates that APL with increased affinities for HLA molecules compared to wild type peptide stimulate CTL specific for wild type peptide from both cancer patients and normal HLA-A*0201 donors. These findings contribute to the development of peptide vaccines for immunotherapeutic treatment modalities.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/280126 |
| Date | January 2002 |
| Creators | Dionne, Sara O. |
| Contributors | Lake, Douglas F. |
| Publisher | The University of Arizona. |
| Source Sets | University of Arizona |
| Language | en_US |
| Detected Language | English |
| Type | text, Dissertation-Reproduction (electronic) |
| Rights | Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. |
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