TY - JOUR
T1 - Downregulation of CD73 associates with T cell exhaustion in AML patients
AU - Kong, Yaxian
AU - Jia, Bei
AU - Zhao, Chenchen
AU - Claxton, David F.
AU - Sharma, Arati
AU - Annageldiyev, Charyguly
AU - Fotos, Joseph S.
AU - Zeng, Hui
AU - Paulson, Robert F.
AU - Prabhu, K. Sandeep
AU - Zheng, Hong
N1 - Funding Information:
This work was supported by the American Society of Hematology (ASH) Scholar Award Grant, the Penn State Cancer Institute (PSCI) and the Penn State University Enhancing Health Initiative, and the Kiesendahl Endowment funding (H.Zheng). R.F.P is funded by USDA-NIFA Hatch project number PEN04581, accession number 1005468.
Publisher Copyright:
© 2019 The Author(s).
PY - 2019/4/24
Y1 - 2019/4/24
N2 - Background: Successful 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. Methods: Peripheral 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. Results: In 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. Conclusions: Our 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.
AB - Background: Successful 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. Methods: Peripheral 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. Results: In 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. Conclusions: Our 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.
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U2 - 10.1186/s13045-019-0728-3
DO - 10.1186/s13045-019-0728-3
M3 - Article
C2 - 31014364
AN - SCOPUS:85064838319
SN - 1756-8722
VL - 12
JO - Journal of Hematology and Oncology
JF - Journal of Hematology and Oncology
IS - 1
M1 - 40
ER -