Improving Antigenic Peptide Vaccines for Cancer Immunotherapy Using a Dominant Tumor-specific T Cell Receptor

• Published in: The Journal of biological chemistry 2013-11, Vol.288 (46), p.33213-33225
• Main Authors: Buhrman, Jonathan D., Jordan, Kimberly R., Munson, Daniel J., Moore, Brandon L., Kappler, John W., Slansky, Jill E.
• Format: Article
• Language: English
• Subjects: Animals; Antigen; Antigens, Neoplasm - immunology; Cancer Vaccines - immunology; Cancer Vaccines - pharmacology; Immunology; Immunotherapy; Mice; Mice, Inbred BALB C; Neoplasm Proteins - immunology; Neoplasms - immunology; Neoplasms - therapy; Peptide Arrays; Peptide Library; Receptors, Antigen, T-Cell - immunology; T Cell; T Cell Receptor; Tumor Immunology; Vaccines
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.509554

Vaccines that incorporate peptide mimics of tumor antigens, or mimotope vaccines, are commonly used in cancer immunotherapy and function by eliciting increased numbers of T cells that cross-react with the native tumor antigen. Unfortunately, they often elicit T cells that do not cross-react with or that have low affinity for the tumor antigen. Using a high affinity tumor-specific T cell clone, we identified a panel of mimotope vaccines for the dominant peptide antigen from a mouse colon tumor that elicits a range of tumor protection following vaccination. The TCR from this high affinity T cell clone was rarely identified in ex vivo evaluation of tumor-specific T cells elicited by mimotope vaccination. Conversely, a low affinity clone found in the tumor and following immunization was frequently identified. Using peptide libraries, we determined if this frequently identified TCR improved the discovery of efficacious mimotopes. We demonstrated that the representative TCR identified more protective mimotopes than the high affinity TCR. These results suggest that targeting a dominant fraction of tumor-specific T cells generates potent immunity and that consideration of the available T cell repertoire is necessary for targeted T cell therapy. These results have important implications when optimizing mimotope vaccines for cancer immunotherapy. Background: Vaccination with mimotopes, peptide mimics of epitopes, stimulates a range of T cell protection. Results: Mimotopes identified from peptide libraries by T cells with common receptors increased immunity more than those with rare high affinity receptors. Conclusion: T cell prevalence must be considered when designing peptide vaccines. Significance: Optimizing mimotopes will improve antigen-specific vaccines for applications including cancer immunotherapies.