Séminaire CIRI : Dr. Jenny VALLADEAU

Dr. Jenny VALLADEAU (CRCL) : "The dendritic cell population cDC1 produce IFN-λ in human primary tumors and are
associated with a good prognosis."

Abstract: Immunotherapies and monoclonal antibodies targeting immune checkpoints have revolutionized cancer therapy. However, only a fraction of patients responds to these treatments. It is therefore crucial to develop new therapeutic strategies to induce or reactivate an efficient anti-tumor immune response. cDC1 dendritic cells are currently under scrutiny, given their extensively-described implication in antitumor immunity and response to immunotherapies in mice. One of their major features is their capacity to produce type III interferon (IFN-III). Indeed, IFN-III share signalling pathways with type I IFN, and experiments conducted in mice have demonstrated an important function for IFN-I in antitumor immune responses.

We have recently highlighted a critical function for type III IFN in shaping the composition of the tumor microenvironment and explaining the strongest positive impact of cDC1 on clinical outcome in many human cancers compared to other DCs subset. By analyzing a large cohort of fresh breast and ovarian primary tumors (n = 107) and transcriptomic public data sets, we have demonstrated that type III IFN represents the predominant IFN in tumors which is specifically produced by cDC1. We further observed that type III IFN or its receptor is associated with a favorable patient outcome in human breast tumors, and more importantly that IFN-III or cDC1 activation through TLR3 triggering directly drives the expression of IL-12p70 and chemokines, which in turn recruit cytotoxic effector cells.

We are now developing multi-IF staining combining 7 markers on FFPE tumor sections permitting a comprehensive analyse of the immune contexture in situ and we are conducting scRNAseq on human tumor infiltrates to identify new immunotherapeutic targets and to better understand the specific functions of each DC subsets.