Equipe d’Accueil : Immune Signaling In Cancer and Infections

Intitulé de l’Unité : Centre de recheerche sur l’inflammation

Nom du Responsable de l’Unité : Valérie PARADIS

Nom du Responsable de l’Équipe : Loredana SAVEANU

Adresse :  16 rue H Huchard 75018 PARIS

Responsable de l’encadrement : Loredana SAVEANU

Tél : …0686604408…  Fax : ……………………… E-mail:  loredana.saveanu@inserm.fr

Résumé du projet (environ une demi-page)

T lymphocytes recognize and kill targets based on interactions between T-cell antigen receptors (TCRs) and tumor- or pathogen-derived antigens bound to major histocompatibility complexes (MHCs) on target cells. This interaction occurs at the plasma membrane of T cells, followed by the endocytosis of the activated TCR. Initially, this process was considered a mechanism of signal extinction. However, this view was challenged by the discovery that internalized TCRs can signal from endocytic compartments.

Our laboratory discovered that the endocytic compartment compatible with TCR signaling is described by the insulin-responsive amino peptidase (IRAP) protein. Deletion of IRAP compromises T cell function. Our published results indicate that TCR signaling triggered from the plasma membrane is sufficient for IL-2 secretion and proliferation at high antigen doses. However, the survival of effector T cells and their ability to infiltrate solid tumors require endosomal TCR signaling (Evnouchidou & Saveanu, Nature Communications, 2020).

Preliminary, unpublished results suggest that endosomal signaling affects the efficiency of « TCR-like » receptors, such as engineered chimeric antigen receptors (CARs). However, this remains to be investigated and confirmed in vivo and in vitro. This M2 project will evaluate the importance of endosomal signaling in CAR function using a combination of in vitro and in vivo approaches. These approaches include characterizing newly engineered CAR-T cells in vitro using flow cytometry, measuring cytokine secretion, and assessing cytotoxicity against targets expressing low or high amounts of the antigen. Finally, we will analyze the efficacy of the newly engineered CAR-T cells in vivo using murine tumor transplant models.

This project will help us understand the mechanisms that control the persistence of effector T cells and their ability to infiltrate target tissues. It may also lead to new ways of engineering CARs that signal more like endogenous TCRs. This could improve CAR-T persistence and efficiency against solid tumors.

 Dernières Publications en lien avec le projet : 

  1. Integrin linked kinase and threonine tyrosine kinase modulate TCR signaling. Caillens V, Boisel E, Ouksel A, Nugue M, Evnouchidou I, Saveanu L. Sci Rep. 2025 Apr 24;15(1):14392. doi: 10.1038/s41598-025-99331-y.
  2. 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.
  3. 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.
  4. 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.
  5. 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.

Ce projet s’inscrit dans la perspective d’une thèse

Type de financement prévu : Concours BioSPC

Ecole Doctorale de rattachement :  BioSPC