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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 : Institut Cochin, Inserm U1016, CNRS UMR8104, Univ. Paris Descartes, SPC
Nom et prénom du Directeur : COURAUD Pierre-Olivier.
Téléphone :
+33 (0)1 40 51 64 57
Télécopie : +33 (0)1 40 51 64 73
Courriel: [email protected]
Renseignements relatifs à l’Equipe :
Nom de l’Equipe d’Accueil : Dynamics of T cell interactions
Nom et prénom du responsable : DONNADIEU Emmanuel (ED) /RANDRIAMAMPITA Clotilde (CR)
Qualité du responsable : DR2 CNRS (ED) / CR1 CNRS (CR)
Téléphone :
+33 (0)1 40 51 64 65
Télécopie : +33 (0)1 40 51 64 55
Courriel : [email protected], [email protected]
Renseignements relatifs au sujet de thèse :
Nom et prénom du Directeur de thèse (HDR) : FEUILLET Vincent
Qualité : CR1 INSERM
Téléphone :
+33 (0)1 40 51 65 56
Télécopie : +33 (0)1 40 51 64 55
Courriel : [email protected]
Titre du sujet proposé :
(En français) Impact des signaux adrénergiques et des β-bloquants sur l’efficacité de la réponse immunitaire
anti-tumorale
(En anglais) Influence of adrenergic signals and β-blockers on the efficiency of anti-tumor immune response
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) :
Several studies have shown the considerable influence of adrenergic signals in cancer. It is generally admitted that
they favour tumor growth by acting directly on the tumor, but they could also act on the anti-tumor immune response.
The objective of the PhD program is to characterize precisely the effects of adrenergic signals on anti-tumor
responses, and to estimate the therapeutic interest of ß–blockers for improving these responses. Confocal imaging,
multicolor flow cytometry and gene expression profiling will be used to address these questions.
Proposition de sujet de thèse à l’appui d’une demande de contrat doctoral 2017-2018
Nom, prénom du directeur de l'unité de recherche : COURAUD Pierre-Olivier
Numéro de l'unité de recherche (et établissement de rattachement) : Institut Cochin, Inserm U1016,
CNRS UMR8104, Univ. Paris Descartes, SPC
Nom, prénom du responsable de l'équipe d'accueil (EAD) : Emmanuel DONNADIEU /Clotilde
RANDRIAMAMPITA
Nom, prénom du directeur de thèse : FEUILLET Vincent
Titre du sujet de thèse proposé : Influence of adrenergic signals and β-blockers on the efficiency of anti-
tumor immune response
Citer 5 mots clés : immune cells, tumor, adrenergic signals, immunotherapy, neuropsychoimmunology
Candidat pressenti :
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OUI
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NON
Contenu scientifique du programme de la thèse (en anglais)
Several studies have shown the considerable influence of the adrenergic signals in numerous pathologies,
including cancer. In humans, retrospective epidemiological studies showed that 1) patients taking ß–blockers
(antagonists of the beta-adrenergic receptors) have significantly lower rates of developing several types of cancers, and 2)
chronic psychological stress, generating strong adrenergic signals, influences the establishment and the evolution of
cancer. It is generally admitted that these signals favour tumor growth by acting directly on the tumor cells, the
angiogenesis and the reshaping of the tumor stroma. In addition, they could also act on the associated anti-tumor
response. This hypothesis is supported by numerous arguments. Firstly, they can regulate the functions of the immune
cells that express adrenergic receptors. Some studies have highlighted global modulations of the anti-tumor response
by adrenergic signals, but few of them aimed at identifying the processes involved. Obviously, the mechanisms that
underlie this phenomenon would deserve a better understanding.
The objective of the PhD program is to characterize precisely the effects of adrenergic signals on the anti-tumor
response, and to estimate the therapeutic interest of ß–blockers for improving this response. Based on our preliminary
results, we will test the hypothesis that adrenergic signals prevent the establishment of an effective anti-tumor response by
interfering with T cell reactivity. To approach this question, we will use two murine tumor models reflecting two types of
situation: 1) a model of vaccine-induced regression of transplanted tumors (TC1) 2) a model of progressing spontaneous
tumors (MMTV-PyMT). In these models, we will estimate the opposite effects of chronic treatments with adrenalin or with
ß–blockers on the various stages of tumor development, and on the cells involved in the establishment of an anti-tumor
response, when such a response is either partially effective (regression model) or in failure (progression model). We will
also estimate the effect of a combined treatment using ß-blockers and an immunotherapy based on an immune checkpoint
inhibitor (anti-PD-1 antibody). Confocal imaging, multicolor flow cytometry and gene expression profiling will be used
to address these questions.
Upon completion of this study, we should better understand the mechanisms of action of the adrenergic signals on the antitumor immune response. It should also allow to assert more clearly if the inhibition of adrenergic signalling by ß-blockers,
alone or combined with others immunotherapies, could have a beneficial effect on patients affected by a cancer.
Indiquez les cinq meilleures publications récentes de l’équipe :
Froehlich J., Versapuech M., Megrelis L., Largeteau Q., Meunier S., Tanchot C., Bismuth G., Delon J., Mangeney M. FAM65B
controls the proliferation of transformed and primary T cells. Oncotarget. (2016) Sep 27;7(39):63215-63225.
Bougherara H, Mansuet-lupo A, Ngô C, Damotte D, Le Frère-Belda MA, Donnadieu E*, & Peranzoni E*. Real-time imaging of
resident T cells in human lung and ovarian carcinomas reveals how different tumor microenvironments control T lymphocyte
migration. Frontiers in Immunology (2015), 6:500.
Thoreau M., Xian LH, KarWai T, Regnier F, Weiss J, Lee B, Johannes L, Dransart E, Le Bon A, Abastado JP, Tartour E,
Trautmann A and Bercovici N. Vaccine-induced tumor regression requires a dynamic cooperation between T cells and myeloid
cells at the tumor site. Oncotarget (2015), 6:27832-46.
Valente M, Baey C, Louche P, Dutertre CA, Vimeux L, Marañón C, Hosmalin A*, Feuillet V*. Apoptotic cell capture by DCs
induces unexpectedly robust autologous CD4+ T-cell responses. Eur J Immunol. (2014), Aug;44(8):2274-86
Salmon, H., K. Franciszkiewicz, D. Damotte, M.-C. Dieu-Nosjean, P. Validire, A. Trautmann, F. Mami-Chouaib, and E. Donnadieu.
Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J. Clin.
Invest. (2012). 122:899–910.