title: High vaccination efficiency of low-affinity epitopes in antitumor immunotherapy.
abstract: Most of the human tumor-associated antigens (TAAs) characterized thus far are derived from nonmutated "self"-proteins. Numerous strategies have been developed to break tolerance to TAAs, combining various forms of antigens with different vectors and adjuvants. However, no study has yet determined how to select epitopes within a given TAA to induce the highest antitumor effector response. We addressed this question by evaluating in HLA-A*0201-transgenic HHD mice the antitumor vaccination efficacy of high- and low-affinity epitopes from the naturally expressed murine telomerase reverse transcriptase (mTERT). Immunity against low-affinity epitopes was induced with heteroclitical variants. We show here that the CTL repertoire against high-affinity epitopes is partially tolerized, while that against low-affinity epitopes is composed of frequent CTLs with high avidity. The high-affinity p797 and p545 mTERT epitopes are not able to protect mice from a lethal challenge with the mTERT-expressing EL4-HHD tumor. In contrast, mice developing CTL responses against the p572 and p988 low-affinity epitopes exhibit potent antitumor immunity and no sign of autoimmune reactivity against TERT-expressing normal tissues. Our results strongly argue for new TAA epitope selection and modification strategies in antitumor immunotherapy applications in humans.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unité 487, Institut Gustave Roussy, Villejuif, France. gross@genethon.fr
authors.forename: David-Alexandre
authors.initials: DA
authors.lastname: Gross
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Graff-Dubois
authors.forename: Paule
authors.initials: P
authors.lastname: Opolon
authors.forename: Sébastien
authors.initials: S
authors.lastname: Cornet
authors.forename: Pedro
authors.initials: P
authors.lastname: Alves
authors.forename: Annelise
authors.initials: A
authors.lastname: Bennaceur-Griscelli
authors.forename: Olivier
authors.initials: O
authors.lastname: Faure
authors.forename: Philippe
authors.initials: P
authors.lastname: Guillaume
authors.forename: Hüseyin
authors.initials: H
authors.lastname: Firat
authors.forename: Salem
authors.initials: S
authors.lastname: Chouaib
authors.forename: François A
authors.initials: FA
authors.lastname: Lemonnier
authors.forename: Jean
authors.initials: J
authors.lastname: Davoust
authors.forename: Isabelle
authors.initials: I
authors.lastname: Miconnet
authors.forename: Robert H
authors.initials: RH
authors.lastname: Vonderheide
authors.forename: Kostas
authors.initials: K
authors.lastname: Kosmatopoulos
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D004268:DNA-Binding Proteins; D000939:Epitopes / Q000276:immunology*; D015234:HLA-A Antigens / Q000276:immunology; D015789:HLA-A2 Antigen; D006801:Humans; D016233:Immunotherapy, Active; D051379:Mice; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D010455:Peptides / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019098:Telomerase / Q000276:immunology
chemical_list: D019496:Cancer Vaccines; D004268:DNA-Binding Proteins; D000939:Epitopes; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D010455:Peptides; C509186:TERT protein, human; D019098:Telomerase; C509187:Tert protein, mouse