High-affinity HLA-A(*)02.01 peptides from parathyroid hormone-related protein generate in vitro and in vivo antitumor CTL response without autoimmune side effects.
Parathyroid hormone-related protein (PTH-rP), a protein produced by prostate carcinoma and other epithelial cancers, is a key agent in the development of bone metastases. We investigated whether the protein follows the self-tolerance paradigm or can be used as a target Ag for anticancer immunotherapy by investigating the immunogenicity of two HLA-A(*)02.01-binding PTH-rP-derived peptides (PTR-2 and -4) with different affinity qualities. PTH-rP peptide-specific CTL lines were generated from the PBMC of two HLA-A(*)02.01(+) healthy individuals, stimulated in vitro with PTH-rP peptide-loaded autologous dendritic cells and IL-2. The peptide-specific CTLs were able to kill PTH-rP(+)HLA-A(*)02.01(+) breast and prostate carcinoma cell lines. The two peptides were also able to elicit a strong antitumor PTH-rP-specific CTL response in HLA-A(*)02.01 (HHD) transgenic mice. The vaccinated mice did not show any sign of side effects due to cell-mediated autoimmunity or toxicity. In this study we describe two immunogenic and toxic-free PTH-rP peptides as valid candidates for the design of peptide-based vaccination strategies against prostate cancer and bone metastases from the most common epithelial malignancies.
Francini
Guido
G
Division of Medical Oncology, Institut National de la Santé et de la Recherche Médicale Unité d'Immunité Cellulaire Antivirale, Institut Pasteur, Paris, France. francini@unisi.it
Scardino
Antonio
A
Kosmatopoulos
Kostas
K
Lemonnier
François A
FA
Campoccia
Giuseppe
G
Sabatino
Marianna
M
Pozzessere
Daniele
D
Petrioli
Roberto
R
Lozzi
Luisa
L
Neri
Paolo
P
Fanetti
Giuseppe
G
Cusi
Maria Grazia
MG
Correale
Pierpaolo
P
D000818:Animals; D015551:Autoimmunity / Q000235:genetics; D001667:Binding, Competitive / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic / Q000379:methods; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D005260:Female; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000628:therapy; D009842:Oligopeptides / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D044162:Parathyroid Hormone-Related Protein; D036361:Peptide Hormones / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology
D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D009842:Oligopeptides; C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein; D036361:Peptide Hormones; D014614:Vaccines, Synthetic