Abstract
BackgroundAcute myeloid leukemia (AML) is an incurable disease with fatal infections or relapse being the main causes of death in most cases. In particular, the severe infections occurring in these patients before or during any treatment suggest an intrinsic alteration of the immune system. In this respect, IL-17-producing T helper (Th17) besides playing a key role in regulating inflammatory response, tumor growth and autoimmune diseases, have been shown to protect against bacterial and fungal pathogens. However, the role of Th17 cells in AML has not yet been clarified.MethodsT cell frequencies were assessed by flow cytometry in the peripheral blood of 30 newly diagnosed AML patients and 30 age-matched healthy volunteers. Cytokine production was determined before and after culture of T cells with either Candida Albicans or AML blasts. Statistical analyses were carried out using the paired and unpaired two-tailed Student’s t tests and confirmed with the non parametric Wilcoxon signed-rank test.ResultsA strong increase of Th17 cells producing immunosuppressive IL-10 was observed in AML patients compared with healthy donors. In addition, stimulation of AML-derived T cells with a Candida albicans antigen induced significantly lower IFN-γ production than that observed in healthy donors; intriguingly, depletion of patient Th17 cells restored IFN-γ production after stimulation. To address the role of AML blasts in inducing Th17 alterations, CD4+ cells from healthy donors were co-cultured with CD33+ blasts: data obtained showed that AML blasts induce in healthy donors levels of IL-10-producing Th17 cells similar to those observed in patients.ConclusionsIn AML patients altered Th17 cells actively cause an immunosuppressive state that may promote infections and probably tumor escape. Th17 cells could thus represent a new target to improve AML immunotherapy.
Highlights
Acute myeloid leukemia (AML) is an incurable disease with fatal infections or relapse being the main causes of death in most cases
We showed that IL-17 T helper (Th17) cells with a double production of IL-17 and IL-10 were strongly increased in AML patients and that ex vivo patient immune response to an infectious antigen, such as Candida Albicans
Alterations in the T cells frequency in peripheral blood of AML patients We first focused on the frequency of CD4+ T cells (Th1, Th2, Th17 and T regulatory (Treg)) in the peripheral blood of 30 newly diagnosed untreated AML patients characterized by karyotype and molecular biology mutations (Table 1) and 30 sex- and age-matched healthy volunteers (HV)
Summary
Acute myeloid leukemia (AML) is an incurable disease with fatal infections or relapse being the main causes of death in most cases. The high frequency and severity of infections (especially fungal) before or during chemotherapy are probably due to a severe adaptive immunity dysfunction directly induced by the disease [5, 6] This immunosuppressive state may be responsible for the continuous recurrence of AML and for the failure of immunotherapies [7], with the exception of allogeneic transplantation [8]. Several studies identified different immunosuppressive mechanisms operating in AML [9,10,11,12,13], the precise link between immune alterations, leukemia immune escape and infections has not yet been elucidated Investigating in this direction, T helper cells seem to be important players with Th17 cells being one of the most intriguing and not fully understood subset so far [14]
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