Avaliação da expressão de células supressoras derivadas de linhagem mielóide antes e após quimioterapia de indução em pacientes pediátricos com leucemia linfoblástica aguda de células precursoras b

Abstract

Acute lymphoblastic leukemia (ALL) is a malignant disease characterized by clonal proliferation and accumulation of progenitor cells that are involved in the differentiation of lymphoid cells in the bone marrow and consequently results in suppression of normal hematopoiesis and replacement of normal elements, affecting other organs such as liver, spleen, lymph nodes, thymus, testis, central nervous system and meninges. Success in the treatment of pediatric B-ALL has increased considerably in recent decades and new treatment and management strategies have achieved a disease-free survival rate of over 90% for pediatric patients. Despite this, many patients experience relapse of the disease after initial response and develop serious complications due to side effects and adverse treatment reactions, which may be associated with immune modulation at the tumor site. In fact, in tumor microenvironment, immunosuppression is a common event and results from the inhibition of activated immune cells and generation of cells with a stronger immunosuppressive capacity, denominated myeloid-derived suppressor cells (MDSCs). MDSCs represent a heterogeneous population of immature myeloid cells (IMCs) that derive from a common myeloid progenitor and possess strong immunosuppressive activity on the functionality of CD8+ T cells and NK cells (natural killer). The presence of these cells in the tumor microenvironment was associated with tumor progression, angiogenesis, local invasion, metastasis and chemotherapeutic resistance. The aim of this study was to evaluate the expression of myeloid-derived suppressor cells (M-MDSCs specifically) before and after induction chemotherapy in pediatric patients with diagnosis of de novo B-cell acute lymphoblastic leukemia (B-ALL) and, moreover, verify whether the chemotherapeutic treatment has any effect on these cells. Peripheral blood (PB) and bone marrow (BM) samples were collected from 15 untreated and randomly pediatric patients. The age ranged from 1 to 17 years, with an average of 8.5 years. The expression of M-MDSCs was evaluated at diagnosis and in the end of induction chemotherapy by flow cytometry. Our data showed an increase of M-MDSCs expression in 60% (9/15) of the patients at the end of the induction therapy, in both evaluated compartments. These data were statistically significant for both bone marrow and peripheral blood analysis, p=0,0012 and p=0,0006, respectively. However, we were not able to associate the increase in M-MDSCS expression with age, gender, risk stratification and genetic findings. In resume, the increase in MMDSC expression was observed in the end of induction chemotherapy, which leads us to believe that these changes probably could have been induced by the inflammatory process engendered by the cytotoxic treatment or by drugs used in the chemotherapy treatment. The data presented in our study suggest that M-MDSCs expression should be evaluated in the next revision of the GBTLI protocol (brazilian group for the treatment of childhood leukemias), since it may be useful to guide new therapeutic approaches contemplating immunomodulatory drugs that act in the depletion of these cells.