ecole doctorale « medicament - L`Institut de Formation Doctorale

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Proposition de sujet de thèse à l’appui d’une demande de contrat doctoral 2017-2018
Renseignements relatifs à l’Unité de Recherche :
Label et intitulé : PARCC INSERM U970
Nom et prénom du Directeur : Alain TEDGUI
Téléphone : 0153988000
Télécopie : 33153987953
Courriel: [email protected]
Renseignements relatifs à l’Equipe :
Nom de l’Equipe d’Accueil : Immuothérapie et traitement anti-angiogénique en cancérologie
Nom et prénom du responsable : Eric TARTOUR
Qualité du responsable : PU-PH
Téléphone : 0156093942
Télécopie : 33156092080
Courriel : [email protected]
Renseignements relatifs au sujet de thèse :
Nom et prénom du Directeur de thèse (HDR) : Corinne TANCHOT
Qualité : Chercheur INSERM
Téléphone : 0153988010
Télécopie : 33153987953
Courriel : [email protected]
Titre du sujet proposé :
(En français) : Optimisation des stratégies de vaccination thérapeutique anti-tumorales par association
avec d’autres stratégies d’immunothérapies.
(En anglais) : Optimization of cancer vaccine therapy by association with other immunotherapies.
Département (cocher le département correspondant au sujet de thèse qui n’est pas obligatoirement le
vôtre) :
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Biologie Cellulaire et moléculaire, Physiologie et Physiopathologie
Immunologie
Développement Génétique Neurobiologie et Vieillissement
Infectiologie, Microbiologie
Summary (5 lines maximum) :
We recently demonstrated the high therapeutic efficacy of a vaccine targeting the specific tumor
associated antigen Survivin. The aim of this project is to evaluate if additional therapies may improve its
efficiency. We will first characterize the expression of various checkpoint inhibitors in vaccinated mice
and the potential anti-angiogenic effect of the survivin vaccine. Following these analyses, we will
associate the survivin vaccine with appropriate checkpoint inhibitors and/or anti-angiogenic molecules.
Proposition de sujet de thèse à l’appui d’une demande de contrat doctoral 2017-2087
Nom, prénom du directeur de l'unité de recherche : Tedgui, Alain
Numéro de l'unité de recherche (et établissement de rattachement) : INSERM U970 Univ Paris Descartes
Nom, prénom du responsable de l'équipe d'accueil (EAD) : Tartour, Eric
Nom, prénom du directeur de thèse : Tanchot, Corinne
Titre du sujet de thèse proposé : Optimization of cancer vaccine therapy by association with other
immunotherapies.
Citer 5 mots clés : Tumor, immunotherapy, Vaccination, Immunosuppression, Angiogenesis
Candidat pressenti :
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OUI
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NON
Contenu scientifique du programme de la thèse (en anglais)
An ideal cancer vaccine must target an antigen, which should be specific and overexpressed on tumor
cells. As such, the inhibitor of apoptosis (IAP) protein survivin is an attractive target for anticancer
immunotherapy because it is a near universally over expressed tumor antigen in human cancers,
whereas its expression is poor or undetectable in most differentiated adult tissues. We recently
developed a survivin-based vaccine strategy composed of long multi-epitopic peptides containing both
promiscuous CD4+ and CD8+ T cell epitopes. We demonstrated the high therapeutic efficacy of this new
vaccine in various mouse tumor models. However a complete tumor regression was not observed in all
animals. In this project we aim to test two additional strategies to improve the efficiency of the survivin
vaccine.
1) Combination of survivin vaccine with immune check-point inhibitors
Although the survivin vaccine improved the anti-tumoral T cell responses, it may not overcome tumor
mediated immunosuppressive mechanisms. We will first study the kinetic of expression of the different
co-inhibitory pathways (PD-1, TIM-3, TIGIT, CTLA-4, PDL-1) in tumor bearing mice vaccinated or not
with survivin. This will be performed by flow cytometry in conventional (CD4+ FoxP3-) and regulatory
(CD4+ FoxP3+) CD4+ T cells and CD8+ T cells isolated from the spleen, draining lymph-nodes and the
tumor. Depending on the results, combinatorial therapy using survivin vaccine and immune checkpoint
blockade (PD-1, TIM-3, etc.) will be performed.
2) Combination of survivin vaccine with anti-angiogenic molecules
Both HIF-1 and VEGF induce an overexpression of survivin by tumor associated endothelial cells,
which thus make them resistant to apoptosis. Such overexpression of survivin promotes angiogenesis
and is associated with a resistance to chemotherapeutic and anti-angiogenic therapies. There is
therefore a strong rational to associate the survivin vaccine with anti-angiogenic molecules.
We will first investigate the direct anti-angiogenic effect of the survivin vaccine by studying blood vessel
in tumor bearing mice vaccinated or not with survivin peptides. This will be performed by multiparametric
in situ immunofluorescence technique and staining with CD31 and -SMA. We will also evaluate the
intensity of survivin expression by endothelial cell isolated from the tumor site by intracellular flow
cytometry staining. We will then combine the survivin vaccine with anti-angiogenic molecules to
strengthen both therapies. A crucial step will be to determine the timing and the order of association of
these two therapies. We aim to address the impact of such treatment on the immune system by deep
functional and phenotypic study of conventional CD4+ T cells, CD8+ T cells and Treg cells isolated from
the spleen, draining lymph-nodes and from the tumor. We will notably take into account the potential
effects of anti-angiogenic molecules on immunosuppression. We will also study the temporal localization
of these different T cell populations in the tumor by confocal analysis.
As a perspective, we will consider to combine immune check-point inhibitors and anti-angiogenic
molecules with survivin vaccine.
Indiquez les cinq meilleures publications récentes de l’équipe :
Terme, M., and C. Tanchot (2017). Ann Pathol 1, 11-17.
Tran, T., et al. (2016). Clin Cancer. Res. 22(16), 4133-4144.
Voron, T., et al. (2015). J Exp Med 212, 139-148.
Tanchot, C., et al. (2013). Cancer Microenviron 6, 147-157.
Meunier, S., et al. (2012). J Leukoc Biol 91, 859-869.