A modified epitope identified for generation and monitoring of PSA-specific T cells in patients on early phases of PSA-based immunotherapeutic protocols.
Efficacy of vaccination in cancer patients on immunotherapeutic protocols can be difficult to evaluate. The aim of this study was therefore to identify a single natural or modified epitope in prostate-specific antigen (PSA) with the ability to generate high levels of PSA-specific T cells to facilitate monitoring in patients after vaccination against prostate cancer. To the best of our knowledge, this study describes for the first time the peptide specificity of T cells stimulated by endogenously processed PSA antigen. The peptide specificity of HLA-A*0201-restricted CD8(+) T cells against human and rhesus PSA was investigated both in vivo after DNA vaccination in HLA-A*0201-transgenic mice and in vitro after repetitive stimulation of human T cells with DNA-transfected human dendritic cells (DCs). One of seven native PSA peptides, psa53-61, was able to activate high levels of PSA-specific CD8(+) T cells in HLA-A*0201-transgenic mice after PSA DNA vaccination. Psa53-61 was also the only peptide that induced human T cells to produce IFNgamma after stimulation with PSA transfected DCs, however not in all donors. Therefore, plasmids encoding modified epitopes in predicted HLA-A*0201 sequences were constructed. One of these modified PSA plasmids consistently induced IFNgamma producing CD8(+) T cells to the corresponding modified peptide as well as to the corresponding native peptide, in all murine and human T cell cultures. This study demonstrates a novel concept of introducing a modified epitope within a self-tumor antigen, with the purpose of eliciting a reliable T cell response from the non-tolerized immune repertoire, to facilitate monitoring of vaccine efficacy in cancer patients on immunotherapeutic protocols. The purpose of such a modified epitope is thus not to induce therapeutically relevant T cells but rather to, in case of weak or divergent T cell responses to self antigens/peptides, help answer questions about efficacy of vaccine delivery and about the possibility to induce immune responses in the selected and often immunosuppressed cancer patients.
Lundberg
Kajsa
K
Department of Oncology and Pathology, Cancer Center Karolinska R8:01, Immune and Gene Therapy Laboratory, Karolinska Institute, 171 76 Stockholm, Sweden. kajsa.lundberg@ki.se
Roos
Anna-Karin
AK
Pavlenko
Maxim
M
Leder
Christoph
C
Wehrum
Diana
D
Guevara-Patiño
José
J
Andersen
Rikke Sick
RS
Pisa
Pavel
P
D000230:Adenocarcinoma / Q000276:immunology / Q000628:therapy; D000595:Amino Acid Sequence; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015234:HLA-A Antigens / Q000235:genetics / Q000378:metabolism; D015789:HLA-A2 Antigen; D006801:Humans; D016233:Immunotherapy, Active / Q000379:methods*; D066298:In Vitro Techniques; D008213:Lymphocyte Activation; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010957:Plasmids / Q000235:genetics; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000628:therapy*; D017386:Sequence Homology, Amino Acid
D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D017430:Prostate-Specific Antigen