High vaccination efficiency of low-affinity epitopes in antitumor immunotherapy

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 det...

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Bibliographic Details
Published in:The Journal of clinical investigation 2004-02, Vol.113 (3), p.425-433
Main Authors: Gross, David-Alexandre, Graff-Dubois, Stéphanie, Opolon, Paule, Cornet, Sébastien, Alves, Pedro, Bennaceur-Griscelli, Annelise, Faure, Olivier, Guillaume, Philippe, Firat, Hüseyin, Chouaib, Salem, Lemonnier, François A, Davoust, Jean, Miconnet, Isabelle, Vonderheide, Robert H, Kosmatopoulos, Kostas
Format: Article
Language:English
Subjects:
Animals
Antigens
Autoimmunity - immunology
Biomedical research
Cancer Vaccines - immunology
Dendritic cells
DNA-Binding Proteins
Epitopes - immunology
HLA-A Antigens - immunology
HLA-A2 Antigen
Humans
Immunotherapy
Immunotherapy, Active
Influenza
Lymphocytes
Mice
Neoplasms - immunology
Neoplasms - therapy
Peptides
Peptides - immunology
Proteins
T cell receptors
T-Lymphocytes, Cytotoxic - immunology
Telomerase
Telomerase - immunology
Thymus gland
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Summary: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.
ISSN:0021-9738
1558-8238
DOI:10.1172/jci200419418