At homeostasis, DCs populations are continuously renewed from bone marrow hematopoietic stem cells. The dynamics of DCs population impacts on immune responses. We aim at understanding: i) the ontogenetic processes enabling the production of various DCs subsets (classical and inflammatory) and its regulation during cancer; ii) how DCs traffic to solid tumours. This project implements contemporary technologies such as high dimensional profiling, single cell RNAseq as well as humanised mice models. Building on a better understanding of DC populations, we design and evaluate therapeutic interventions aiming at increasing DC infiltration in solid tumours to stimulate anti-tumour immunity.
2- Antigen cross-presentation/presentation by MHCI/II.
In most instances, induction of antigen-specific T cell responses relies on the phagocytosis of particulate antigens by DCs. This is highly relevant for tumour antigens that are engulfed together with cancer cell debris. The dynamics of antigen-containing phagosomes is controlled by their interactions with multiple types of endosomes (early, storage, late, lysosomes). These interactions ultimately control the formation and presentation of antigenic peptides-MHC I and II complexes. We investigate if and how phagosome-associated proteins control phagosome dynamics and antigen presentation by MHCI/II to T lymphocytes in DCs subsets. Both, unbiased genetic screen using CRISPR-Cas9 and hypothesis driven approaches (Rab GTPases and PI3Kinases) are developed in the lab to tackle the molecular cell biology of antigen presentation by DCs.
3- T lymphocyte activation, fate and function.
The recognition of MHC-peptide complex by the T cell receptor leads to the formation of the immune synapse. We aim at understanding how intracellular trafficking in T lymphocytes supports the recognition of MHC-peptides complexes by the T cell receptor. Using intracellular live imaging, advanced microscopy techniques (FRET) and cutting-edge proteomics (in vivo biotynilation via APEX2), we investigate the endocytic mechanisms controlling TCR signalling at the DC-T cell synapse. Specifically, we are addressing how the balance between recycling or degradation of several key proteins for T cell activation such as TCRzeta, Lck and LAT controls signalling downstream TCR triggering.
In addition, we investigate the long-term consequences of antigen presentation by DCs subsets on the differentiation, fate and function of T lymphocytes. DCs are composed of multiple subsets which are also regulated by context-dependent signals. We are investigating how cell-intrinsic DCs features and environmental cues (including factors from the tumour micro-environment) shape the diversity of antigen-presenting DCs and anti-tumour T cell responses. In particular, we investigate how DCs imprint some trafficking behaviour in T cells and impact on T cell fate in the context of breast and lung cancer.