Abstract
CD4+CD25+Foxp3+ regulatory T cells (Tregs) accumulate in bone marrow microenvironment in acute myeloid leukemia (AML). However, little is known about how the tumor environment including tumor cells themselves affects this process. Here we demonstrated that AML cells expressed inducible T-cell costimulator ligand (ICOSL) that can provide costimulation through ICOS for the conversion and expansion of Tregs sustaining high Foxp3 and CD25 expression as well as a suppressive function. TNF-a stimulation up-regulated the expression of ICOSL. Furthermore, both the conversion and expansion of CD4+CD25+Foxp3+ T cells and CD4+ICOS+Foxp3+ T cells were induced by co-culture with AML cells overexpressed ICOSL. CD4+CD25+ICOS+ T cells possessed stronger ability to secrete IL-10 than CD4+CD25+ICOS− T cells. The mechanism by which IL-10 promoted the proliferation of AML cells was dependent on the activation of the Akt, Erk1/2, p38, and Stat3 signaling pathways. Blockade of ICOS signaling using anti-ICOSL antibody impaired the generation of Tregs and retarded the progression of an AML mice model injected with C1498 cells. The expression of ICOSL of patient AML cells and ICOS+ Tregs were found to be predictors for overall survival and disease-free survival in patients with AML, with ICOS+ Treg cell subset being a stronger predictor than total Tregs. These results suggest that ICOSL expression by AML cells may directly drive Treg expansion as a mechanism of immune evasion and ICOS+ Treg cell frequency is a better prognostic predictor in patients with AML.
Highlights
Acute myeloid leukemia (AML) is a genetically complex and heterogeneous set of diseases characterized by overwhelming accumulation of immature myeloid cells in the bone marrow and peripheral blood
We determined whether three other cytokines IFN-γ, IL10, IL-17A or IL-21 affect the expression of inducible T-cell costimulator ligand (ICOSL) and found that these four cytokines did not change the expression of ICOSL on two acute myeloid leukemia (AML) cell lines HL-60 and HEL (Figure S1)
Since it has been recognized that the level of TNF-α is elevated in AML patients [24, 25], we speculate that the expression of ICOSL on AML cells can be enhanced in vivo
Summary
Acute myeloid leukemia (AML) is a genetically complex and heterogeneous set of diseases characterized by overwhelming accumulation of immature myeloid cells in the bone marrow and peripheral blood. In AML, we have demonstrated that 11.9% of the CD4+ T cells found in bone marrow are CD25+CD127lo, with only 9.19% found in the peripheral blood of the same patients [9]. These results indicate that AML cells attract and retain Tregs in the bone marrow, or that the tumor microenvironment can promote the expansion of tumorinfiltrating Tregs. It has been reported that the tumor microenvironment can favor the conversion of inducible Tregs from CD4+CD25−T cells [10], with the total pool of Tregs being comprised of both natural Tregs and induced peripheral Tregs
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