CD73 on cancer-associated fibroblasts enhanced by the A2B-mediated feedforward circuit enforces an immune checkpoint

Miao Yu; Gang Guo; Lei Huang; Libin Deng; Chang Sheng Chang; Bhagelu R. Achyut; Madison Canning; Ningchun Xu; Ali S. Arbab; Roni J. Bollag; Paulo C. Rodriguez; Andrew L. Mellor; Huidong Shi; David H. Munn; Yan Cui

doi:10.1038/s41467-019-14060-x

CD73 on cancer-associated fibroblasts enhanced by the A_2B-mediated feedforward circuit enforces an immune checkpoint

Miao Yu, Gang Guo, Lei Huang, Libin Deng, Chang Sheng Chang, Bhagelu R. Achyut, Madison Canning, Ningchun Xu, Ali S. Arbab, Roni J. Bollag, Paulo C. Rodriguez, Andrew L. Mellor, Huidong Shi, David H. Munn, Yan Cui

Research output: Contribution to journal › Article › peer-review

122 Scopus citations

Abstract

CD73, an ecto-5′-nucleotidase (NT5E), serves as an immune checkpoint by generating adenosine (ADO), which suppresses immune activation through the A_2A receptor. Elevated CD73 levels in tumor tissues correlate with poor clinical outcomes. However, the crucial source of CD73 activity within the tumor microenvironment remains unspecified. Here, we demonstrate that cancer-associated fibroblasts (CAFs) constitute the prominent CD73^hi population in human colorectal cancers (CRCs) and two CD73⁻ murine tumor models, including a modified CRC. Clinically, high CAF abundancy in CRC tissues correlates strongly with elevated CD73 activity and poor prognosis. Mechanistically, CAF-CD73 expression is enhanced via an ADO-A_2B receptor-mediated feedforward circuit triggered by tumor cell death, which enforces the CD73-checkpoint. Simultaneous inhibition of A_2A and A_2B pathways with CD73-neutralization synergistically enhances antitumor immunity in CAF-rich tumors. Therefore, the strategic and effective targeting of both the A_2B-mediated ADO-CAF-CD73 feedforward circuit and A_2A-mediated immune suppression is crucial for improving therapeutic outcomes.

Original language	English (US)
Article number	515
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-14060-x
State	Published - Dec 1 2020

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41467-019-14060-x

Cite this

Yu, M., Guo, G., Huang, L., Deng, L., Chang, C. S., Achyut, B. R., Canning, M., Xu, N., Arbab, A. S., Bollag, R. J., Rodriguez, P. C., Mellor, A. L., Shi, H., Munn, D. H., & Cui, Y. (2020). CD73 on cancer-associated fibroblasts enhanced by the A_2B-mediated feedforward circuit enforces an immune checkpoint. Nature communications, 11(1), Article 515. https://doi.org/10.1038/s41467-019-14060-x

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title = "CD73 on cancer-associated fibroblasts enhanced by the A2B-mediated feedforward circuit enforces an immune checkpoint",

abstract = "CD73, an ecto-5′-nucleotidase (NT5E), serves as an immune checkpoint by generating adenosine (ADO), which suppresses immune activation through the A2A receptor. Elevated CD73 levels in tumor tissues correlate with poor clinical outcomes. However, the crucial source of CD73 activity within the tumor microenvironment remains unspecified. Here, we demonstrate that cancer-associated fibroblasts (CAFs) constitute the prominent CD73hi population in human colorectal cancers (CRCs) and two CD73− murine tumor models, including a modified CRC. Clinically, high CAF abundancy in CRC tissues correlates strongly with elevated CD73 activity and poor prognosis. Mechanistically, CAF-CD73 expression is enhanced via an ADO-A2B receptor-mediated feedforward circuit triggered by tumor cell death, which enforces the CD73-checkpoint. Simultaneous inhibition of A2A and A2B pathways with CD73-neutralization synergistically enhances antitumor immunity in CAF-rich tumors. Therefore, the strategic and effective targeting of both the A2B-mediated ADO-CAF-CD73 feedforward circuit and A2A-mediated immune suppression is crucial for improving therapeutic outcomes.",

author = "Miao Yu and Gang Guo and Lei Huang and Libin Deng and Chang, {Chang Sheng} and Achyut, {Bhagelu R.} and Madison Canning and Ningchun Xu and Arbab, {Ali S.} and Bollag, {Roni J.} and Rodriguez, {Paulo C.} and Mellor, {Andrew L.} and Huidong Shi and Munn, {David H.} and Yan Cui",

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AU - Guo, Gang

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AU - Deng, Libin

AU - Chang, Chang Sheng

AU - Achyut, Bhagelu R.

AU - Canning, Madison

AU - Xu, Ningchun

AU - Arbab, Ali S.

AU - Bollag, Roni J.

AU - Rodriguez, Paulo C.

AU - Mellor, Andrew L.

AU - Shi, Huidong

AU - Munn, David H.

AU - Cui, Yan

PY - 2020/12/1

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N2 - CD73, an ecto-5′-nucleotidase (NT5E), serves as an immune checkpoint by generating adenosine (ADO), which suppresses immune activation through the A2A receptor. Elevated CD73 levels in tumor tissues correlate with poor clinical outcomes. However, the crucial source of CD73 activity within the tumor microenvironment remains unspecified. Here, we demonstrate that cancer-associated fibroblasts (CAFs) constitute the prominent CD73hi population in human colorectal cancers (CRCs) and two CD73− murine tumor models, including a modified CRC. Clinically, high CAF abundancy in CRC tissues correlates strongly with elevated CD73 activity and poor prognosis. Mechanistically, CAF-CD73 expression is enhanced via an ADO-A2B receptor-mediated feedforward circuit triggered by tumor cell death, which enforces the CD73-checkpoint. Simultaneous inhibition of A2A and A2B pathways with CD73-neutralization synergistically enhances antitumor immunity in CAF-rich tumors. Therefore, the strategic and effective targeting of both the A2B-mediated ADO-CAF-CD73 feedforward circuit and A2A-mediated immune suppression is crucial for improving therapeutic outcomes.

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