Investigate the role of endosomal signaling in chimeric antigen receptors (CAR) function
Responsable du Stage : Loredana SAVEANU
Mail : email@example.com
Faculté de Médecine X Bichat
Résumé du Projet de Stage
The recognition and the killing of targets by the T lymphocytes is based on the interaction of T cell antigen receptors (TCR) with tumor or pathogen-derived antigenic peptides bound to major histocompatibility complexes (MHC) of target cells. TCR – MHC interaction takes place at plasma membrane of T cells and is followed by the endocytosis of activated TCR, which was initially considered to be a mechanism of signal extinction. This initial view was challenged by the discovery that the internalized TCR is able to signal from endocytic compartments.
Our laboratory found that the endocytic compartment compatible with TCR signaling is tagged by Insulin Responsive AminoPeptidase (IRAP), whose deletion compromises T cell function. Our published results indicate that TCR signaling triggered from plasma membrane is sufficient for IL-2 secretion and proliferation, but the effector T cell survival and their ability to infiltrate solid tumors requires endosomal TCR signaling (Evnouchidou I…Saveanu L, Nat Commun 2020).
Which TCR signaling modules are triggered from the plasma membrane and which are triggered from endosomes is not yet known. Preliminary unpublished results suggest that endosomal signaling also seems to affect the efficiency of “TCR-like” receptors, such as the engineered chimeric antigen receptors (CAR), but its importance is untested. The project will evaluate the importance of endosomal signaling in TCR and CAR function by a combination of in vitro and in vivo approaches, such as in situ biotinylation coupled with quantitative mass-spectrometry and murine transplanted tumor models.
By the identification and validation of the signaling pathways that are triggered from endosomal compartments by both TCR and CARs this project: – will help to understand the mechanisms that control the persistence of effector T cells and their ability to infiltrate target tissues; – might open new ways for engineering better CARs, whose signaling is more similar to that of endogenous TCR, in order to improve CAR-T persistence and efficiency against solid tumors.
1- The role of endocytic trafficking in antigen T Cell Receptor activation. Evnouchidou I, Caillens V, Koumantou D, Saveanu L. Biomed J. 2021 Sep 27:S2319-4170(21)00129-3. doi: 10.1016/j.bj.2021.09.004.
2- The Role of Insulin Regulated Aminopeptidase in Endocytic Trafficking and Receptor Signaling in Immune Cells. Descamps D, Evnouchidou I, Caillens V, Drajac C, Riffault S, van Endert P, Saveanu L. Front Mol Biosci. 2020 Oct 20;7:583556. doi: 10.3389/fmolb.2020.583556.
3- IRAP-dependent endosomal T cell receptor signalling is essential for T cell responses. Evnouchidou I, Chappert P, Benadda S, Zucchetti A, Weimershaus M, Bens M, Caillens V, Koumantou D, Lotersztajn S, van Endert P, Davoust J, Guermonprez P, Hivroz C, Gross DA, Saveanu L. Nat Commun. 2020 Jun 2;11(1):2779. doi: 10.1038/s41467-020-16471-7
4- Is there a place and role for endocytic TCR signaling? Saveanu L, Zucchetti AE, Evnouchidou I, Ardouin L, Hivroz C. Immunol Rev. 2019 Sep;291(1):57-74. doi: 10.1111/imr.12764.
5-IRAP+ endosomes restrict TLR9 activation and signaling. Babdor J, Descamps D, Adiko AC, Tohmé M, Maschalidi S, Evnouchidou I, Vasconcellos LR, De Luca M, Mauvais FX, Garfa-Traore M, Brinkmann MM, Chignard M, Manoury B, Saveanu L. Nat Immunol. 2017 May;18(5):509-518. doi: 10.1038/ni.3711.
Ce projet s’inscrit-il dans la perspective d’une thèse :
si oui type de financement prévu : Concours ED
Ecole Doctorale de rattachement : BioSPC
Intitulé de l’Unité : Antigen Presentation to T cells
Nom du Responsable de l’Unité : Pr Renato MONTEIRO
Nom du Responsable de l’Équipe :Loredana SAVEANU
Adresse : Faculté de Médecine X Bichat 16 rue H Huchard 75018 PARIS