Characterization of the tumor and its microenvironment in chronic lymphocytic leukemia

The following proposal aims at investigating the interactions between chronic lymphocytic leukemia (CLL) B-cellsand their microenvironment, with a focus on T cells in particular regulatory T lymphocytes (Tregs). CLL is the mostfrequent hematologic malignancy in Europe. Despite recent advances in the standard of care, there is still nocurative therapeutic option. We recently characterized the tumor microenvironment of a murine modelrecapitulating the features of the human CLL (Eμ-TCL1 mice) and from this work hypothesized that highly activatedTregs could be inhibited in order to reactivate anti-tumor immunity. In human, the natural microenvironment of CLLB-cells is the lymph node. To get further insights in the Tregs found in this organ, we will perform single-cellanalyses (RNA sequencing and mass cytometry) of a large collection of primary lymph nodes collected from CLLpatients, allowing the detailed analysis of T cell populations in this environment. In addition, topographic maps ofcells and markers will be obtained from CLL LN by imaging mass cytometry. We will now also better characterizeTregs in the murine model, and using a conditional knock-out system, we will analyze the role of two transcriptionfactors involved in the cell-microenvironment communication (AHR and HIF1alpha) which are suspected to becrucial for highly activated Tregs. Finally, as the access to patient lymph node remains limited in this disease, wewill set-up a patient-derived xenograft mouse model with primary CLL cells to test therapies in vivo. Thesecomplementary approaches will improve our understanding of the interaction between leukemic B cells and Tcells/Tregs in the LN and will reveal new options for patient stratification and treatment.