High vaccination efficiency of low-affinity epitopes in antitumor immunotherapy
David-Alexandre Gross, … , Robert H. Vonderheide, Kostas Kosmatopoulos
David-Alexandre Gross, … , Robert H. Vonderheide, Kostas Kosmatopoulos
Published February 1, 2004
Citation Information: J Clin Invest. 2004;113(3):425-433. https://doi.org/10.1172/JCI19418.
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Article Immunology

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

David-Alexandre Gross, Stéphanie Graff-Dubois, Paule Opolon, Sébastien Cornet, Pedro Alves, Annelise Bennaceur-Griscelli, Olivier Faure, Philippe Guillaume, Hüseyin Firat, Salem Chouaib, François A. Lemonnier, Jean Davoust, Isabelle Miconnet, Robert H. Vonderheide, Kostas Kosmatopoulos

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Quality of the mTERT epitope–specific CTL repertoire. From 5 to 10 mice ...
Quality of the mTERT epitope–specific CTL repertoire. From 5 to 10 mice were vaccinated with the high-affinity p545 and p797, the heteroclitical p572Y and p988Y, or the nonself controls p876 and fluM58 peptides. Results represent the mean per group and are expressed as mean ± SEM. (a) CTL frequency was evaluated ex vivo 11 days after vaccination by a standard 24-hour IFN-γ ELISPOT assay with cognate native peptides. Spot-forming units (SFUs) for 106 CD8+ splenocytes are represented. (b) Avidity of CTLs after 1 week of in vitro restimulation was defined by measuring the normalized concentration of native peptide that gives 50% of maximal lysis (KC50). The normalized concentration was the ratio of peptide concentration to the RA. CTL frequency and KC50 were compared using the nonparametric Mann-Whitney U test; asterisks in a and b indicate values that were considered significant (P < 0.05). (c) Peripheral blood mononuclear cells from naive or immunized mice 11 days earlier were stained with specific PE-coupled HLA-A*0201/p797 or (d) HLA-A*0201/p572Y tetramer together with anti-CD8–APC, anti-TCRβ–CyChrome, and anti-CD44–FITC. Representatives staining gated in TCRβ+ CD44+ are shown.