Alterações em células dendríticas derivadas de monócitos e em monócitos de pacientes com câncer de mama

Abstract

Breast cancer is an important cause of morbidity and mortality in Brazil and worldwide. New therapeutic strategies have been proposed and one of them is the use of cell therapy with dendritic cells (DCs), however, the literature regarding the real benefit of this approach shows great variability and inability to produce a lasting immunity. In this paper we made a detailed characterization of monocyte-derived dendritic cells (MoDCs) of patients with breast cancer and monocytes that originated them. A lower yield of MoDCs was obtained from patients when compared to age matched healthy controls. Patient MoDCs exhibited decreased expressions of maturation and activation markers. Furthermore, cultures of MoDCs of patients had significantly elevated levels of spontaneous production of IL-6, which is consistent with a pro-tumor phenotype. These differences in molecule expression and cytokine production led us to postulate that the signaling pathways and / or the expression of toll like receptors (TLRs) could be altered. A decrease of TLR9 and TLR2 and an increase in the expression of NFkBp50 was found in MoDCs of patients without stimulation. After stimulation with LPS and CPG the patients did not upregulate expression of MyD88, suggesting a downregulation of the signaling pathways activated by these molecular patterns. The number of monocytes was also were decreased in patients, showing a reduced expression of GM-CSF receptors compared to monocytes of healthy controls. Cytokine production by monocytes from cancer patients was also altered, with an increased production of IL-6, IL-4 and IL-10. TLR2 and TLR9 expression was downregulated in monocytes of patients. Together these data show that monocytes are already altered in patients with cancer, and that will influence the phenotype of DCs differentiated from them. Tumor burden seems to induce a tolerogenic and pro-tumoral phenotype in patients´cells. This finding is important for the development of DC-based cancer immunotherapy.