Abstract

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.

Original languageEnglish (US)
Article number40
JournalJournal of Hematology and Oncology
Volume12
Issue number1
DOIs
StatePublished - Apr 24 2019

Fingerprint

Acute Myeloid Leukemia
Down-Regulation
T-Lymphocytes
Adenosine
Neoplasms
Flow Cytometry
Leukemia
Cytokines
Tumor Microenvironment
Cellular Structures
Adenosine Monophosphate
Stromal Cells
Immunity
Therapeutics
Observation
Apoptosis
Antibodies

All Science Journal Classification (ASJC) codes

  • Hematology
  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

@article{4609406182fe49fd8afd579c572318eb,
title = "Downregulation of CD73 associates with T cell exhaustion in AML patients",
abstract = "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.",
author = "Yaxian Kong and Bei Jia and Chenchen Zhao and David Claxton and Arati Sharma and Charyguly Annageldiyev and Joseph Fotos and Hui Zeng and Robert Paulson and Prabhu, {Kumble Sandeep} and Hong Zheng",
year = "2019",
month = "4",
day = "24",
doi = "10.1186/s13045-019-0728-3",
language = "English (US)",
volume = "12",
journal = "Journal of Hematology and Oncology",
issn = "1756-8722",
publisher = "BioMed Central",
number = "1",

}

Downregulation of CD73 associates with T cell exhaustion in AML patients. / Kong, Yaxian; Jia, Bei; Zhao, Chenchen; Claxton, David; Sharma, Arati; Annageldiyev, Charyguly; Fotos, Joseph; Zeng, Hui; Paulson, Robert; Prabhu, Kumble Sandeep; Zheng, Hong.

In: Journal of Hematology and Oncology, Vol. 12, No. 1, 40, 24.04.2019.

Research output: Contribution to journalArticle

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

AU - Sharma, Arati

AU - Annageldiyev, Charyguly

AU - Fotos, Joseph

AU - Zeng, Hui

AU - Paulson, Robert

AU - Prabhu, Kumble Sandeep

AU - Zheng, Hong

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.

UR - http://www.scopus.com/inward/record.url?scp=85064838319&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85064838319&partnerID=8YFLogxK

U2 - 10.1186/s13045-019-0728-3

DO - 10.1186/s13045-019-0728-3

M3 - Article

VL - 12

JO - Journal of Hematology and Oncology

JF - Journal of Hematology and Oncology

SN - 1756-8722

IS - 1

M1 - 40

ER -