Characterization of tumor reactive CD8 T cells induced by peptide vaccination in melanoma patients

Détails

Ressource 1Télécharger: BIB_37B85855305B.P001.pdf (7593.40 [Ko])
Etat: Public
Version: Après imprimatur
ID Serval
serval:BIB_37B85855305B
Type
Mémoire
Sous-type
(Mémoire de) maîtrise (master)
Collection
Publications
Institution
Titre
Characterization of tumor reactive CD8 T cells induced by peptide vaccination in melanoma patients
Auteur(s)
Rufer N.
Directeur(s)
Romero P.
Détails de l'institution
Université de Lausanne, Faculté de biologie et médecine
Statut éditorial
Acceptée
Date de publication
2011
Langue
anglais
Nombre de pages
46
Résumé
ABSTRACT¦Naturally acquired tumor-specific T-cells can be detected in most advanced cancer patients.¦Yet, they often fail to control or eliminate the disease, in contrast to many virus-specific CD8¦T lymphocytes. Therapeutic vaccines aim at inducing and boosting specific T-cells mediated¦immunity to reduce tumor burden. The properties of CD8 T-cells required for protection from¦infectious disease and cancer are only partially characterized.¦The objectives of this study were to assess effector functions, stage of differentiation and¦clonotype selection of tumor-reactive T lymphocytes following peptide vaccination in¦melanoma patients over time. Results were compared to protective viral-specific T-cell¦responses found in healthy individuals. We also characterized dominant versus low/non¦dominant T-cell clonotypes with the aim to further understand the in vivo function of each set¦of frequency-based specific T-cells.¦Here we developed and applied a novel approach for molecular and functional analysis of¦single T lymphocytes ex vivo. T-cell receptor (TCR) clonotype mapping revealed rapid¦selection and expansion of co-dominant T-cell clonotypes, which made up the majority of the¦highly differentiated "effector" T-cells, but only 25% of the less differentiated "effectormemory"¦cells, mostly composed of non-dominant clonotypes. Moreover, we show that¦advanced effector cell differentiation was indeed clonotype-dependent. Surprisingly, however,¦the acquisition of effector functions (cytokine production, killing) was clonotype-independent.¦Vaccination of melanoma patients with native peptide induced competent effector function in¦both dominant and non-dominant clonotypes, suggesting that most if not all clonotypes¦participating in a T-cell response have the potential to develop equal functional competence.¦In contrast, many T-cells remained poorly functional after vaccination with analog peptide,¦despite similar clonotype-dependent differentiation. Our findings show that the type of¦peptide vaccine has a critical influence on the selection and functional activation of the¦clonotypic T-cell repertoire. They also show that systematic assessment of individual T-cells¦identifies the cellular basis of immune responses, contributing to the rational development of¦vaccines.
Mots-clé
Human, melanoma, vaccination, EBV, CMV, CD8 T-cells, single-cell, differentiation, TCR repertoire, clonotype, gene expression, protein expression, cytolysis, molecular biology
Création de la notice
13/07/2012 14:14
Dernière modification de la notice
20/08/2019 14:26
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