Elise CHIFFOLEAU

Our team scientific activity is committed to basic and translational research and aims at better understanding the mechanisms of immune tolerance and the role of dendritic cells (DCs) in immunoregulation in order to identify new cellular and molecular therapeutic targets. Recently, the theme has then been expanded to the role of DCs and Mononuclear Phagocytes (MNP) in inflammatory diseases and in host-virus interactions in the context of transplantation and immunodepression.

We further developed new functional genomic approaches to better characterize MNP diversity and their role in immunopathology. This strategy to enlarge our research topics and expertise aimed to increase the interdisciplinarity of the team and allowed new funding opportunities (H2020, EU/ERA NET, ITN INSTRUCT, iSITE NEXT). There is also a strong commitment to translational research and clinical development with filed patents industrial partnerships.

Recently, we contributed to the understanding of the molecular basis of immunoregulatory MNP functions in transplantation (Cell Metabolism, 2019) anti-tumor immunity (Cancer Cell 2019, Blood adv. 2017, Front Immunol 2020) and inflammatory diseases (Mucosal Immunol, 2016; J Immunol, 2017; Cell 2019) as well macrophages in lung infection (Nat Immunol 2020). We also demonstrated our ability to translate some of our findings to the clinic (The Lancet 2020).
 

We showed that the orphan C-type Lectin receptor CLEC-1 acts in DCs as an immune checkpoint during sterile inflammation by preventing IL-12 expression and downstream CD4+ T cell activation (Lopez-Robles et al. Blood Adv 2017) (patent EP16306381). Our recent data suggest that CLEC-1 binds to DAMP(s) released by secondary necrotic cells and prevents the cross-presentation of dead cell-associated antigens to CD8+ T cells by conventional DC1. Consequently, CLEC-1 blockade enhanced anti-tumor responses in vivo and we observed a synergistic effect in combination with cytotoxic chemotherapy inducing CLEC-1 ligand release (patents EP 19306584.4 19306583.6). We now aim to study in depth the molecular mechanisms of the CLEC-1 checkpoint in mouse and human MNP in immunopathology by using functional genomics approaches. Particularly, we aim to identify the specific CLEC-1 ligand(s) and to decipher the role of CLEC-1 in MNP in subsequent T cell activation and anti-tumor responses by using experimental mouse models and scRNAseq approaches. Furthermore, in a translational program with the biotech OSEI, we aim to generate antihuman CLEC-1 mAbs to investigate CLEC-1 expression in human tumor MNPs and its role on MNP phagocytosis and cell activation. Finally, we will evaluate in human CLEC-1 KI mice the therapeutic value of hCLEC-1 antagonists in pre-clinical models of cancer. In parallel, we aim to investigate the function of CLEC-1 in MNP in resolution of inflammation in tissue damage models of liver intoxication by Acetaminophen, of DSS-induced colitis and of E. Coli induced pneumonia (collaboration A Roquilly, Nantes) to pave the way for potential applications in broader diseases.

Staff: M Drouin (phD student, 100% FTE), J Saenz (Postdoc 100%FTE)

Collaborations: OSE Immunotherapeutics biotech (Nantes), G Brown (Exeter, UK), A Roquilly (Nantes).

Funding: Collaborative contract with OSE including CIFRE thesis (2016-2021), ANR PRCE (2019-2022), LIGUE (2021).