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

Author

Listed:
  • Miao Yu

    (Augusta University)

  • Gang Guo

    (Augusta University)

  • Lei Huang

    (Newcastle University)

  • Libin Deng

    (Nanchang University)

  • Chang-Sheng Chang

    (Augusta University)

  • Bhagelu R. Achyut

    (Augusta University)

  • Madison Canning

    (Augusta University)

  • Ningchun Xu

    (Augusta University)

  • Ali S. Arbab

    (Augusta University)

  • Roni J. Bollag

    (Augusta University)

  • Paulo C. Rodriguez

    (H. Lee Moffitt Cancer Center and Research Institute)

  • Andrew L. Mellor

    (Newcastle University)

  • Huidong Shi

    (Augusta University)

  • David H. Munn

    (Augusta University)

  • Yan Cui

    (Augusta University)

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.

Suggested Citation

  • 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 Sh, 2020. "CD73 on cancer-associated fibroblasts enhanced by the A2B-mediated feedforward circuit enforces an immune checkpoint," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-14060-x
    DOI: 10.1038/s41467-019-14060-x
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    Cited by:

    1. Ankur Chakravarthy & Ian Reddin & Stephen Henderson & Cindy Dong & Nerissa Kirkwood & Maxmilan Jeyakumar & Daniela Rothschild Rodriguez & Natalia Gonzalez Martinez & Jacqueline McDermott & Xiaoping Su, 2022. "Integrated analysis of cervical squamous cell carcinoma cohorts from three continents reveals conserved subtypes of prognostic significance," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Jingjing Qi & Hongxiang Sun & Yao Zhang & Zhengting Wang & Zhenzhen Xun & Ziyi Li & Xinyu Ding & Rujuan Bao & Liwen Hong & Wenqing Jia & Fei Fang & Hongzhi Liu & Lei Chen & Jie Zhong & Duowu Zou & Lia, 2022. "Single-cell and spatial analysis reveal interaction of FAP+ fibroblasts and SPP1+ macrophages in colorectal cancer," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

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