Acute Myeloid Leukemia Cells Express ICOS Ligand to Promote the Expansion of Regulatory T Cells

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.

Inducible T‐cell co‐stimulator: Signaling mechanisms in T follicular helper cells and beyond

“…Furthermore, melanoma patients who received high‐dose IL‐2 therapy exhibited a selective expansion of ICOS + Treg populations which correlated with poor prognosis . Similarly, human acute myeloid leukemia cells expressing high levels of ICOSL promote Treg responses . Second, ICOS promotes the expansion, survival, and cytokine production of inflammatory lung ILC2 cells in animal models of asthma .…”

Acute Myeloid Leukaemia in Its Niche: the Bone Marrow Microenvironment in Acute Myeloid Leukaemia

“…They have been found to work in conjunction with AML by creating a localized zone where HSPC can reside on the endosteal surface and improve their survival [58]. Studies have shown accumulation of Tregs in the bone marrow in AML [59]. Han et al showed that AML can express a Treg costimulatory ligand ICOS-L, activating Tregs directly, and they can also induce some CD4 + cells to become inducible Tregs.…”

A Bump in the Road: How the Hostile AML Microenvironment Affects CAR T Cell Therapy

“…The AML microenvironment favors the expansion of Tregs (37,(63)(64)(65). Expression of inducible T cell co-stimulator ligand (ICOSL) on AML blasts stimulates T cells through inducible T cell costimulator (ICOS), leading to differentiation to Treg phenotype and expansion of the Treg subset (66). Additionally, AML blasts and bone marrow mesenchymal cells overexpress IDO, which promotes the emergence of a Treg phenotype and limits T cell proliferation (67).…”

“…While the presence of AML blasts can stimulate monocytes to secrete proinflammatory cytokines including tumor necrosis factor-α (TNFα), IL1β, and IL6, they also cause increased production of the anti-inflammatory cytokine IL10 (93). Additionally, increased Treg subsets contribute to production of IL10 and transforming growth factor β (TGF-β), which can limit the effector function of CAR T cells (66). In analysis of CD123-CAR T cells targeting AML, TNF-α and IFN-γ upregulate CD123 expression on endothelial cells, increasing risk for capillary leak.…”