Extracellular Vesicles in Chronic Lymphocytic Leukemia: Tumor Microenvironment Messengers as a Basis for New Targeted Therapies?

SIMPLE SUMMARY: Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of abnormal B lymphocytes in the peripheral components of the immune system. Despite the development of new therapies for CLL, drug resistance and disease relapse still occur. In the bone marrow and secondary lymphoid tissues, the trafficking, survival, and proliferation of leukemic B cells are regulated by interactions with the microenvironment (via cell-extracellular matrix interactions, cell-cell contacts, and the exchange of soluble factors) and contribute to treatment resistance. Here, we review the biology of the extracellular vesicles released into this microenvironment with cross-talk between neoplastic B cells and neighboring or remote target cells. A better understanding of the extracellular vesicles’ role in CLL progression and drug resistance might open up opportunities for the development of novel therapeutics that target the pro-survival dialogue between tumor cells and the tumor microenvironment. ABSTRACT: In addition to intrinsic genomic and nongenomic alterations, tumor progression is also dependent on the tumor microenvironment (TME, mainly composed of the extracellular matrix (ECM), secreted factors, and bystander immune and stromal cells). In chronic lymphocytic leukemia (CLL), B cells have a defect in cell death; contact with the TME in secondary lymphoid organs dramatically increases the B cells’ survival via the activation of various molecular pathways, including the B cell receptor and CD40 signaling. Conversely, CLL cells increase the permissiveness of the TME by inducing changes in the ECM, secreted factors, and bystander cells. Recently, the extracellular vesicles (EVs) released into the TME have emerged as key arbiters of cross-talk with tumor cells. The EVs’ cargo can contain various bioactive substances (including metabolites, proteins, RNA, and DNA); upon delivery to target cells, these substances can induce intracellular signaling and drive tumor progression. Here, we review recent research on the biology of EVs in CLL. EVs have diagnostic/prognostic significance and clearly influence the clinical outcome of CLL; hence, from the perspective of blocking CLL-TME interactions, EVs are therapeutic targets. The identification of novel EV inhibitors might pave the way to the development of novel combination treatments for CLL and the optimization of currently available treatments (including immunotherapy).