Projet ANR-07-BLAN-0199 – TSTRFA : Influence of tumor microenvironment on T cell recruitment and functioning.
Programme : Blanc (BLANC) 2007
Année de financement : 2007
Coordinateur du projet : Monsieur Salem CHOUAIB (INSERM ADR PARIS XI VILLEJUIF)
Partenaires : Institut national de la santé et de la recherche médicale; Institut national de la santé et de la recherche médicale
Montant : 272000.0 euros
Date de début : 2008
Durée : 24 mois
Résumé : Anti-cancer therapies aim at targeting tumour specific processes to eliminate tumour cells. Recent years have seen an increase in the efforts of trying to develop therapies that are tumour-specific and non-genotoxic. One approach to develop novel therapies is to exploit the fact that the immune system has the capacity to distinguish between normal cells and neoplastic cells. Such cell-based immune therapies have fewer side effects than existing conventional therapies and promise to be more specific towards cancer cells. Unfortunately, such expectations are rarely fulfilled and so far, immunotherapy approaches have been of limited success. This is probably correlated with an inefficient local anti-tumour cytotoxic response and also due to the strategies used by tumour cells to escape from the immune system. To destroy established tumors, CTLs must traffic to and infiltrate the tumor stroma and must be activated at the tumor site to develop appropriate effector mechanisms such as killing and cytokine secretion. Anti-tumor failure of the immune system may be due to a combination of factors acting on each one of these steps. This project aims to investigate two of them, i.e., T cell recruitment within tumors and mechanisms modulating T cell efficiency within the tumor microenvironment. -  The first objective of our project will be to design experiments, in which the role of chemokines in recruiting T cells in human tumors, will be directly measured. For this purpose, we will investigate CTL migration within tumours with a set of complementary approaches using in vitro and in vivo xenogeneic murine models to identify chemokines and chemokine receptors involved in this process. We will also analyse the behaviour of T cells in the native tumour microenvironment or in reconstituted cell systems in 3D collagen. -  The tumor microenvironment is responsible not only for T cell recruitment, but also for the modulation of T cell activity within the tumor. We recently demonstrated that interaction of the integrin aE(CD103)b7, often expressed by TIL, with the epithelial cell marker E-cadherin on tumor cell, is required for cytolytic granule polarization and subsequent exocytosis to trigger an effective tumor cell lysis,. Our results also indicated that TGF-b1, abundant at the tumor microenvironment, plays a crucial role in this induction. -  The second main objective of the project will be therefore focused on the understanding of the mechanisms used by CD103 to promote cytotoxicity. We will investigate CD103 adhesion and signalling properties associated with the regulation of cell-mediated cytotoxicity as well as the mechanisms by which TGF-b1 regulates CD103 expression in the tumor microenvironment. The signalling events induced by the simultaneous engagement of TCR and TGF-b1 receptors on the Smad family and their transcriptional consequences will be also adressed. -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       ...