Equipe d’Accueil : Régulation des fonctions effectrices des lymphocytes T

Intitulé de l’Unité : Institut Cochin, CNRS UMR8104, INSERM U1016, Université Paris Cité

Nom du Responsable de l’Unité : Florence Niedergang

Nom du Responsable de l’Équipe : Bruno Lucas

Adresse : Bâtiment Gustave Roussy 8ème étage, 27, rue du Faubourg Saint Jacques, 75014 PARIS

Responsable de l’encadrement : Bruno Lucas

Tél : 06 21 87 20 99  Fax : 01 40 51 65 35  E-mail: bruno.lucas@inserm.fr

Résumé du projet 

Anti-tumor immune responses are often deficient in cancer patients. Although demonstrated as effective, immunotherapies such as anti-PD1 monoclonal antibodies, which aim to reactivate lymphocyte responses, are efficient only in 20 to 30% patients. Recent findings in the team suggest that the Tumor Necrosis Factor (TNF) may participate to T-cell exhaustion in the tumor microenvironment. Indeed, on one hand, the MC38 tumor cell line initially develops similarly after transplantation into Wild-Type (WT) and TNF Knock-Out (TNFKO) mice and then tends to regress in nearly half of TNFKO mice. On the other hand, memory T cells from aged TNFKO mice exhibit lower expression of inhibitory receptors (PD1, LAG-3, TIM-3, TIGIT) than T cells from aged Wild Type mice. Using the CRISPR/Cas9 technology, we have generated MC38 cells unable to produce TNF. Interestingly, all TNFKO mice injected with MC38 TNKO cells completely rejected tumor cells. Following these results, the present Master 2 project will aim to study TNF-induced T-cell exhaustion in tumor-infiltrating T cells (TILs). We will focus on 4 main axes: (i) extend our preliminary results to other tumor models (other tumor cell lines such as B16, and EL4 versus the AOM/DSS induced colitis-associated colorectal cancer), (ii) compare the phenotype of TILs from MC38 TNFKO versus MC38 WT tumors (in particular we will assess the expression of inhibitory receptors by TILs and their ability to produce cyokines, perforin and granzyme, (iii) decipher the molecular mechanisms involved in TNF-induced T-cell exhaustion and (iv) test whether anti-TNF therapy may synergize with anti-PD1 immunotherapy in cancer models. The team has the expertise and all the necessary mouse lines to carry out this project and has access to all Cochin Institute facilities. This project will contribute to a better in vivo understanding of mechanisms involved in T cell exhaustion and could pave the way for the development of new immunological tools to counter resistance to current treatments.

 

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

Type de financement prévu : Bourse

 Ecole Doctorale de rattachement :  ED 562 BioSpc

Dernières Publications en lien avec le projet :

  1. Guichard V., N. Bonilla, A. Durand, A. Audemard-Verger, T. Guilbert, B. Martin, B. Lucas*, and C. Auffray*. 2017. Calcium-mediated shaping of naive CD4 T-cell phenotype and function. Elife 6. pii: e27215. (CA and BL contributed equally to this paper).
  2. Durand A., A. Audemard-Verger, V. Guichard, R. Mattiuz, A. Delpoux, P. Hamon, N. Bonilla, M. Rivière, J. Delon, B. Martin, C. Auffray, A. Boissonnas, and B. Lucas. 2018. Profiling the lymphoid-resident T cell pool reveals modulation by age and microbiota. Nature Communications 9:68.
  3. Audemard-Verger A., E. Pillebout, A. Jamin, L. Berthelot, C. Auffray, B. Martin, A. Sannier, E. Daugas, J. Déchanet-Merville, Y. Richard, R. Monteiro and B. Lucas. 2019. Recruitment of CXCR3+ T cells into injured tissues in adult IgA vasculitis patients correlates with disease activity. J Autoimmun 99:73.
  4. Durand A., N. Bonilla, T. Level, Z. Ginestet, A. Lombès, …, B. Lucas. 2024. Type 1 interferons and Foxo1 down-regulation play a key role in age-related T-cell exhaustion in mice. Nature Communications 15:1718.
  5. Porte S, Audemard-Verger A, Wu C, Durand A, Level T, Giraud L, Lombès A, Germain M, Pierre R, Saintpierre B, Lambert M, Auffray C, Peyssonnaux C, Goldwasser F, Vaulont V, Alves-Guerra MC, Dentin R, Lucas B* and Martin B*. 2024. Iron boosts anti-tumor type 1 T-cell responses and anti-PD1 1 immunotherapy. Cancer Immunology Research 12:1252. (Bruno Lucas and Bruno Martin contributed equally to this paper).