Abstract
BackgroundSuccessful treatment for acute myeloid leukemia (AML) remains challenging. Inhibiting immune checkpoint to enhance anti-tumor response is an attractive strategy for effective leukemia therapeutics. CD73 is a recently recognized immune checkpoint mediator that is highly expressed on tumor cells and stromal cells in tumor microenvironment. The ectonucleotidase activity of CD73 catalyzes AMP to adenosine, which subsequently inhibits anti-tumor immune responses. In this study, we aim to explore the effect of CD73 in AML.MethodsPeripheral blood samples collected from patients with newly diagnosed AML (n = 27) were used in this study. CD73 expression on each immune cell component was examined by flow cytometry. Phenotypic study of CD73-expressing T cells and analysis of the correlation between CD73 and other immune checkpoints were performed using flow cytometry-based assays. Functional status of CD73+ vs. CD73− T cells was assessed in an in vitro cytokine release assay upon CD3/CD28 antibody stimulation.ResultsIn contrast to the long recognized immune suppressive effect of CD73-adenosine signaling in tumor tissue, we made a striking observation that in AML, CD73 expression on CD8 T cells associates with an increased immune response. CD73+ CD8 T cells are more functional, whereas CD73− CD8 T cells exhibit features of exhaustion manifested by high expression of inhibitory receptors such as PD-1 and TIGIT, increased intracellular expression of Eomes, reduced capacity of cytokine production, and high susceptibility to apoptosis.ConclusionsOur data highlight the potential of CD73 as a double-edged sword in anti-leukemia immunity and argue strongly for the combinational treatment by adding immune checkpoint inhibitors to the CD73-targeting approaches.
Highlights
Recent FDA approval of eight novel agents in the last 2 years has significantly expanded options for treatment of acute myeloid leukemia (AML) [1–7]
CD73 is highly expressed on CD8 T cells in peripheral blood from AML patients To determine which cell components express CD73 in a patient with AML, peripheral blood mononuclear cells (PBMCs) were assessed for CD73 expression by flow cytometry gated on markers for blast (CD45int, low SSC), Treg (CD45hiCD4+CD25+), CD4, CD8, NK (CD45hiCD3−CD56+), monocytes (CD45hiCD11b+CD14hi/low), and dendritic cells (DCs; CD45hiCD3−CD19−CD56−CD14−HLA-DR+)
Low CD73 expression on CD8 T cells associates with high leukemia burden We focused our study on CD8 T cells and compared the expression of CD73 in AML (n = 27) vs. healthy controls (n = 16)
Summary
Recent FDA approval of eight novel agents in the last 2 years has significantly expanded options for treatment of acute myeloid leukemia (AML) [1–7]. A variety of additional leukemia therapeutics targeting specific genetic mutations or cellular processes are emerging [8–14]. Despite these exciting advances, successful treatment of AML remains challenging with 5-year survival of only 27.4% according to the National Cancer Institute (NCI). Daver et al have recently reported a promising result from an early clinical trial treating AML patients with a combination of azacitidine and nivolumab, the first approved PD-1-targeting agent [34]. Inhibiting immune checkpoint to enhance anti-tumor response is an attractive strategy for effective leukemia therapeutics. We aim to explore the effect of CD73 in AML
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