Reprogramming of the leukemic microenvironment by small extracellular vesicles: from characterization totherapeutic application

Small extracellular vesicles (sEV) represent an important part of the cell-to-cell communication. The impact of sEVon the tumor microenvironment was proven in several cancer types, including hematologic malignancies. They playa key role in promoting cancer as they influence multiple tumor-related functions as cellular proliferation, migration,and metastasis. They can also impair an efficient anti-tumor immune response. Yet, many sEV cargoes remainunknown and the cellular modifications they induce still need to be elucidated.Here we designed a project dedicated to study these mechanisms in vivo in the context of chronic lymphocyticleukemia using several transgenic murine models. We will first study the composition of sEV, dissect themechanisms enabling their uptake in various types of target cells ex vivo and in vivo, and finally test inhibitors orneutralizing antibodies to block their negative effects in vivo in mice. In a second part, we will study their functionalimpact on the immune system leading to tumor evasion, by focusing on molecules such as immune checkpointligands, ncRNA, and membrane-anchored cytokines. Finally, we will focus on understudied cargoes such asmetabolites. Preliminary data indicated the presence of several metabolites and associated metabolic enzymes insEV. We will investigate their occurrence and study the consequences on metabolic activity of target cells to revealnew directions for the development of innovative therapies. Altogether, this project will allow the identification of new druggable candidates for cancer and pursue sEV-basedtargeted therapy strategies, to foster the progress towards a more effective anti-tumor immune respon