Análise da modulação das células dendríticas por vesículas extracelulares do sangue de pacientes com Leucemia Linfocítica Crônica

Abstract

Chronic Lymphocytic Leukemia (CLL) is a hematological disease that has a higher incidence in males over the age of 65. CLL is characterized by increased proliferation of mature B lymphocytes in the bone marrow, which accumulate in the peripheral blood, lymph nodes and lymphatic system, with CD5+ as the main marker. Leukemic lymphocytes have various mechanisms capable of modulating the immune system. One of the mechanisms involved in this modulation occurs through the release of extracellular vesicles (EVs). They carry various biomolecules from the cell of origin in order to alter the functions of target cells, including immune cells, and promote conditions for the development of an immunosuppressive microenvironment characteristic of cancer diseases, which affects the prognosis and survival of patients. To assess the impact of EVs on immune response modulation, we evaluated the phenotype of healthy monocytes differentiated into dendritic cells (moDCs) in the presence of EVs isolated from primary culture of PBMCs from patients with CLL or healthy donors. Subsequently, the moDCs were cocultured with allogeneic T lymphocytes to assess their ability to activate the adaptive immune response. We observed that EVs from patients with CLL induced a decrease in important moDC markers, such as integrin (CD11c), co-stimulatory molecules (CD80 and CD86) and MHC class II (HLA-DR), which are important for cell activation and induction of T lymphocyte proliferation. When moDCs differentiated with EVs from patients with CLL were cocultured with allogeneic T lymphocytes in a mixed lymphocyte reaction, we observed a decrease in the pro-inflammatory cytokines TNF and IFNg, as well as an increase in the anti-inflammatory cytokine IL-10, when compared to moDCs differentiated with EVs from healthy donors, supporting a pro-tumor tolerogenic status induced by EVs from patients with CLL. In this context, it can be observed that EVs from patients with CLL were able to suppress the adaptive immune response, apparently contributing to a tolerogenic and permissive profile for the tumor.