The CD73 immune checkpoint promotes tumor cell metabolic fitness
- Centre Hospitalier de l'Université de Montréal, Canada
- McGill University, Canada
- Université de Montréal, Canada
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.
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All data generated or analyzed during this study are included in the manuscript and supporting file.
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Author details
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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The CD73 immune checkpoint promotes tumor cell metabolic fitness
eLife 12:e84508.
https://doi.org/10.7554/eLife.84508
