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    Migration and function of T cells in tumors

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    Principal investigator : Emmanuel Donnadieu

    Contact : emmanuel.donnadieu@inserm.fr – Tel : +33 1 40 51 65 64

     

    Objective

    Even if the immune system is able to respond against cancer, in growing tumors T lymphocytes usually fail to kill malignant cells. By using advanced imaging techniques, we have made significant progress in the understanding of how T cells are blocked in their antitumor activities and revealed a default in the ability of T cells to contact tumor cells. In our project, we will continue to explore the reasons that limit T cells from massively infiltrating tumors, with a special attention to the influence of the extracellular matrix as well as tumor-associated macrophages.

    The group

    In 2015, this group is composed of two post-doctoral scientists, Elisa Peranzoni (SIRIC-CARPEM) and Houcine Bougherara (partnership with a private company, GammaMabs Pharma) and Emmanuel Donnadieu (DR2, CNRS).

    Research Interests

    Recent years have seen the emergence of novel cancer immunotherapies based on our increasing knowledge of molecules involved in the regulation of T cell responses. Although some patients show an impressive survival response, response rates usually remain low, and it is now well accepted that multiple mechanisms suppressing anti-tumor immune functions take place in the tumor microenvironment.

    Our previous results obtained in progressing human tumors demonstrate that T cells are rarely in contact with tumor cells and therefore unable to directly kill these cells (Salmon, J. Clin. Invest. 2012). This failure represents a major obstacle to T-cell based immunotherapy. Our projects aim to identify the different obstacles that block T cells in their antitumor activities. The role of the extracellular matrix as well as tumor-associated macrophages is currently investigated.  We are also extending our research to the influence of the tumor on draining lymph nodes and investigate the basis and consequences of tumor-induced draining lymph nodes alterations on T cell activation and trafficking.

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    T cells (green) plated on human lung tumor slices kept in live accumulate and migrate actively in the stroma (red). Conversely, tumor regions (blue) contain very few T cells that hardly migrate. Video that shows a 20 min recording.

    Since 2012, we have an ongoing collaboration with a biotech company, GammaMabs Pharma, to study the mode of action of a therapeutic monoclonal antibody (anti-AMHR2) in ovarian cancer.

    Most of our experiments rely on the use of powerful and original approaches: confocal and two-photon microscopy, a preparation of tissue slices kept in live (Salmon, JoVE 2011), relevant mouse tumor models and ongoing collaborations with clinicians.

    The method of tissue slices combined with dynamic imaging microscopy is described in details in this video.

     

    Main publications and presentations

    • Donnadieu, E (2014). Defects in T cell migration within tumors: a role for extracellular matrix architecture. Annual Meeting 2014 of the American Association of Cancer Research. Webcast of the presentation
    • Peranzoni E, Rivas-Caicedo A, Bougherara H, Salmon H, Donnadieu E. Positive and negative influence of the matrix architecture on antitumor immune surveillance. Cell Mol Life Sci. 2013; 70(23):4431-48.
    • 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. 
    • Asperti-Boursin F, Real E, Bismuth G, Trautmann A, Donnadieu E. (2007). CCR7 ligands control basal T cell motility within lymph node slices in a phosphoinositide 3-kinase- independent manner. J. Exp. Med. 2007 204:1167-79

     

    Financial supports

    These projects are supported by la Ligue Contre le Cancer (Equipe Labellisée Ligue Contre le Cancer), les sites de recherche intégré sur le cancer (SIRIC) – Cancer Research for Personalized Medicine (CARPEM) and the biotech company GammaMabs Pharma.

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