Mapping and binding analysis of peptides derived from the tumor-associated antigen survivin for eight HLA alleles
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Published on: March 24, 2015
Margaret M Bachinsky1, Darlene E Guillen, Sima R Patel
1Department of Immunotherapeutics, Purdue Pharma, Cranbury, NJ, USA.
Abstract:
There is considerable interest in developing immunotherapeutic approaches to elicit tumor-specific CTL responses in cancer patients. Epitope-based approaches aim to deliver the antigenic peptides or epitopes recognized by CTLs rather than the intact tumor antigen. Many tumor-associated proteins are nonmutated self proteins for which the dominant peptide epitopes are usually poorly immunogenic. The subdominant epitopes, however, can elicit robust T cell responses if optimized for their ability to bind to class I MHC molecules. Only the epitopes for a few tumor antigens expressed in human cancers have been defined to this level, mainly for technical reasons. The means to rapidly screen and characterize the binding of epitopes derived from complex tumor-associated antigens is an important enabling technology. Here, we have used the high-throughput technology iTopia to identify those peptides derived from the tumor-associated antigen survivin that bind 8 class I alleles. A library of overlapping nonamers spanning the length of the survivin protein was initially screened for peptides capable of binding each allele. Nineteen HLA-A*0201, zero HLA-A*0101, seven HLA-A*0301, twelve HLA-A*1101, twenty-four HLA-A*2402, six HLA-B*0702, six HLA-B*0801, and eight HLA-B*1501 binding peptides were identified based on an arbitrary cutoff. Peptides capable of binding a given allele were further characterized by their affinity for MHC class I molecules and by the rate of dissociation of the complex. This information should help guide functional studies and future epitope-based immunotherapies.
Insights
Developing cancer immunotherapies requires identifying effective tumor epitopes. This study used high-throughput screening to find survivin peptides that bind to specific human leukocyte antigen (HLA) class I alleles, aiding future epitope-based treatments.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Immunotherapy aims to induce tumor-specific T cell responses for cancer treatment.
- Epitope-based vaccines deliver specific antigenic peptides to stimulate cytotoxic T lymphocytes (CTLs).
- Identifying immunogenic epitopes from self-proteins like survivin is challenging due to low immunogenicity.
Purpose of the Study:
- To develop a high-throughput method for screening tumor antigen-derived peptides.
- To identify survivin-derived peptides that bind to multiple human leukocyte antigen (HLA) class I alleles.
- To characterize the binding affinity and dissociation rates of identified peptides for guiding immunotherapy.
Main Methods:
- Utilized the iTopia high-throughput screening platform.
- Screened a library of overlapping nonamers from the survivin protein against eight HLA class I alleles.
- Characterized peptide binding affinity and dissociation rates for selected binders.
Main Results:
- Identified numerous survivin-derived peptides binding to HLA-A*0201, HLA-A*0301, HLA-A*1101, HLA-A*2402, HLA-B*0702, HLA-B*0801, and HLA-B*1501 alleles.
- No binding peptides were found for the HLA-A*0101 allele under the tested conditions.
- Detailed characterization of binding affinity and dissociation kinetics was performed.
Conclusions:
- The iTopia platform enables rapid identification and characterization of HLA class I binding peptides from tumor antigens.
- This approach facilitates the discovery of novel epitopes for survivin-based cancer immunotherapies.
- The identified peptides provide a foundation for further functional studies and the development of effective immunotherapeutic strategies.
