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Identification and characterization of a human agonist cytotoxic T-lymphocyte epitope of human prostate-specific antigen.
Clin Cancer Res. 2002 Jan; 8(1):41-53.CC

Abstract

One potential target of vaccine therapy for human prostate cancer is the prostate-specific antigen (PSA). One strategy to enhance the immunogenicity of a self-antigen such as PSA is to develop agonist epitopes that are potentially more immunogenic. The studies described here report the design and analysis of an agonist epitope designated PSA-3A ("A" for agonist) of the PSA-3 CTL epitope. Studies demonstrate that when compared with the native PSA-3 epitope, the PSA-3A agonist demonstrates enhanced binding to the MHC class I A2 allele as well as enhanced stability of the peptide-MHC complex. T-cell lines generated with either the PSA-3 or the PSA-3A peptide showed higher levels of lysis of targets pulsed with the PSA-3A peptide than those targets pulsed with the PSA-3 peptide; this was observed when both the concentration of peptide and the ratio of effector to target cells were titrated. T cells stimulated with dendritic cells (DCs) pulsed with PSA-3A peptide produced higher levels of IFN-gamma than did DCs pulsed with PSA-3 peptide; however, no increase in apoptosis was seen in T cells stimulated with the PSA-3A agonist compared with those stimulated with PSA-3. Human T-cell lines generated with the PSA-3A agonist had the ability to lyse human prostate carcinoma cells expressing native PSA in an MHC-restricted manner. Recombinant vaccinia viruses were also constructed that contained the entire PSA transgene with and without the single amino acid change that constitutes the PSA-3A epitope; DCs infected with the recombinant vector containing the agonist amino acid change within the entire PSA gene (designated rV-PSA-3A) were more effective than DCs infected with the rV-PSA vector in enhancing IFN-gamma production by T cells. Finally, the PSA-3A agonist was shown to induce higher levels of T-cell activation, compared with the PSA-3 peptide, in an in vivo model using HLA-A2.1/K(b) transgenic mice. These studies thus demonstrate the potential use of the PSA-3A agonist epitope in both peptide- and vector-mediated immunotherapy protocols for prostate cancer.

Authors+Show Affiliations

Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

11801539

Citation

Terasawa, Hiroshi, et al. "Identification and Characterization of a Human Agonist Cytotoxic T-lymphocyte Epitope of Human Prostate-specific Antigen." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 8, no. 1, 2002, pp. 41-53.
Terasawa H, Tsang KY, Gulley J, et al. Identification and characterization of a human agonist cytotoxic T-lymphocyte epitope of human prostate-specific antigen. Clin Cancer Res. 2002;8(1):41-53.
Terasawa, H., Tsang, K. Y., Gulley, J., Arlen, P., & Schlom, J. (2002). Identification and characterization of a human agonist cytotoxic T-lymphocyte epitope of human prostate-specific antigen. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 8(1), 41-53.
Terasawa H, et al. Identification and Characterization of a Human Agonist Cytotoxic T-lymphocyte Epitope of Human Prostate-specific Antigen. Clin Cancer Res. 2002;8(1):41-53. PubMed PMID: 11801539.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification and characterization of a human agonist cytotoxic T-lymphocyte epitope of human prostate-specific antigen. AU - Terasawa,Hiroshi, AU - Tsang,Kwong-Yok, AU - Gulley,James, AU - Arlen,Philip, AU - Schlom,Jeffrey, PY - 2002/1/22/pubmed PY - 2002/4/12/medline PY - 2002/1/22/entrez SP - 41 EP - 53 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin. Cancer Res. VL - 8 IS - 1 N2 - One potential target of vaccine therapy for human prostate cancer is the prostate-specific antigen (PSA). One strategy to enhance the immunogenicity of a self-antigen such as PSA is to develop agonist epitopes that are potentially more immunogenic. The studies described here report the design and analysis of an agonist epitope designated PSA-3A ("A" for agonist) of the PSA-3 CTL epitope. Studies demonstrate that when compared with the native PSA-3 epitope, the PSA-3A agonist demonstrates enhanced binding to the MHC class I A2 allele as well as enhanced stability of the peptide-MHC complex. T-cell lines generated with either the PSA-3 or the PSA-3A peptide showed higher levels of lysis of targets pulsed with the PSA-3A peptide than those targets pulsed with the PSA-3 peptide; this was observed when both the concentration of peptide and the ratio of effector to target cells were titrated. T cells stimulated with dendritic cells (DCs) pulsed with PSA-3A peptide produced higher levels of IFN-gamma than did DCs pulsed with PSA-3 peptide; however, no increase in apoptosis was seen in T cells stimulated with the PSA-3A agonist compared with those stimulated with PSA-3. Human T-cell lines generated with the PSA-3A agonist had the ability to lyse human prostate carcinoma cells expressing native PSA in an MHC-restricted manner. Recombinant vaccinia viruses were also constructed that contained the entire PSA transgene with and without the single amino acid change that constitutes the PSA-3A epitope; DCs infected with the recombinant vector containing the agonist amino acid change within the entire PSA gene (designated rV-PSA-3A) were more effective than DCs infected with the rV-PSA vector in enhancing IFN-gamma production by T cells. Finally, the PSA-3A agonist was shown to induce higher levels of T-cell activation, compared with the PSA-3 peptide, in an in vivo model using HLA-A2.1/K(b) transgenic mice. These studies thus demonstrate the potential use of the PSA-3A agonist epitope in both peptide- and vector-mediated immunotherapy protocols for prostate cancer. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/11801539/Identification_and_characterization_of_a_human_agonist_cytotoxic_T_lymphocyte_epitope_of_human_prostate_specific_antigen_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=11801539 DB - PRIME DP - Unbound Medicine ER -