Inducible Hsp70 as target of anticancer immunotherapy: Identification of HLA-A*0201-restricted epitopes.
The design of a broad application tumor vaccine requires the identification of tumor antigens expressed in a majority of tumors of various origins. We questioned whether the major stress-inducible heat shock protein Hsp70 (also known as Hsp72), a protein frequently overexpressed in human tumors of various histological origins, but not in most physiological normal tissues, constitutes a tumor antigen. We selected the p391 and p393 peptides from the sequence of the human inducible Hsp70 that had a high affinity for HLA-A*0201. These peptides were able to trigger a CTL response in vivo in HLA-A*0201-transgenic HHD mice and in vitro in HLA-A*0201+ healthy donors. p391- and p393-specific human and murine CTL recognized human tumor cells overexpressing Hsp70 in a HLA-A*0201-restricted manner. Tetramer analysis of TILs showed that these Hsp70 epitopes are targets of an immune response in many HLA-A*0201+ breast cancer patients. Hsp70 is a tumor antigen and the Hsp70-derived peptides p391 and p393 could be used to raise a cytotoxic response against tumors of various origins.
Faure
Olivier
O
INSERM U487, Institut Gustave Roussy, Villejuif, France. olivier.faure@mines-paris.org
Graff-Dubois
Stéphanie
S
Bretaudeau
Laurent
L
Derré
Laurent
L
Gross
David-Alexandre
DA
Alves
Pedro M S
PM
Cornet
Sébastien
S
Duffour
Marie-Thérèse
MT
Chouaib
Salem
S
Miconnet
Isabelle
I
Grégoire
Marc
M
Jotereau
Francine
F
Lemonnier
François A
FA
Abastado
Jean-Pierre
JP
Kosmatopoulos
Kostas
K
D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D019556:COS Cells; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D000939:Epitopes / Q000737:chemistry; D006680:HLA Antigens / Q000737:chemistry; D015234:HLA-A Antigens / Q000737:chemistry*; D015789:HLA-A2 Antigen; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000951:Antigens, Neoplasm; D000939:Epitopes; D006680:HLA Antigens; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D018840:HSP70 Heat-Shock Proteins; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma