1. Cancer Biology

The CD73 immune checkpoint promotes tumor cell metabolic fitness

  1. David Allard
  2. Isabelle Cousineau
  3. Eric H Ma
  4. Bertrand Allard
  5. Yacine Bareche
  6. Hubert Fleury
  7. John Stagg  Is a corresponding author
  1. Centre Hospitalier de l'Université de Montréal, Canada
  2. McGill University, Canada
  3. Université de Montréal, Canada
https://doi.org/10.7554/eLife.84508
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  1. David Allard
  2. Isabelle Cousineau
  3. Eric H Ma
  4. Bertrand Allard
  5. Yacine Bareche
  6. Hubert Fleury
  7. John Stagg
(2023)
The CD73 immune checkpoint promotes tumor cell metabolic fitness
eLife 12:e84508.
https://doi.org/10.7554/eLife.84508
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Abstract

CD73 is an ectonucleotidase overexpressed on tumor cells that suppresses anti-tumor immunity. Accordingly, several CD73 inhibitors are currently being evaluated in the clinic, including in large randomized clinical trials. Yet, the tumor cell-intrinsic impact of CD73 remain largely uncharacterized. Using metabolomics, we discovered that CD73 significantly enhances tumor cell mitochondrial respiration and aspartate biosynthesis. Importantly, rescuing aspartate biosynthesis was sufficient to restore proliferation of CD73-deficient tumors in immune deficient mice. Seahorse analysis of a large panel of mouse and human tumor cells demonstrated that CD73 enhanced oxidative phosphorylation (OXPHOS) and glycolytic reserve. Targeting CD73 decreased tumor cell metabolic fitness, increased genomic instability and suppressed poly ADP ribose polymerase (PARP) activity. Our study thus uncovered an important immune-independent function for CD73 in promoting tumor cell metabolism, and provides the rationale for previously unforeseen combination therapies incorporating CD73 inhibition.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting file.

Article and author information

Author details

  1. David Allard

    Centre Hospitalier de l'Université de Montréal, Montreal, Canada
    Competing interests
    No competing interests declared.

  2. Isabelle Cousineau

    Centre Hospitalier de l'Université de Montréal, Montreal, Canada
    Competing interests
    No competing interests declared.

  3. Eric H Ma

    Department of Physiology, McGill University, Montreal, Canada
    Competing interests
    No competing interests declared.

  4. Bertrand Allard

    Centre Hospitalier de l'Université de Montréal, Montreal, Canada
    Competing interests
    No competing interests declared.

  5. Yacine Bareche

    Centre Hospitalier de l'Université de Montréal, Montreal, Canada
    Competing interests
    No competing interests declared.

  6. Hubert Fleury

    Centre Hospitalier de l'Université de Montréal, Montreal, Canada
    Competing interests
    No competing interests declared.

  7. John Stagg

    Faculté de Pharmacie, Université de Montréal, Montreal, Canada
    For correspondence
    john.stagg@umontreal.ca
    Competing interests
    John Stagg, is permanent member of the Scientific Advisory Board and owns stocks of Surface Oncology, is member of the Scientific Advisory Board of Tarus Therapeutics, and is a member of the Scientific Advisory Board of Domain Therapeutics..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7833-4228

Funding

Canadian Institutes of Health Research

  • John Stagg

Fonds de recherche du Québec

  • John Stagg

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All the experimental procedures were authorized, and all animals were handled according to an approved Institutional Animal Care and Use Committee (IACUC) protocol (#C20010JSs) of the Centre de Recherche du Centre Hospitalier de l'Université de Montréal.

Copyright

© 2023, Allard et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. David Allard
  2. Isabelle Cousineau
  3. Eric H Ma
  4. Bertrand Allard
  5. Yacine Bareche
  6. Hubert Fleury
  7. John Stagg
(2023)
The CD73 immune checkpoint promotes tumor cell metabolic fitness
eLife 12:e84508.
https://doi.org/10.7554/eLife.84508

Share this article

https://doi.org/10.7554/eLife.84508

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