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

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.

Metrics

  • 1,801
    views
  • 242
    downloads
  • 3
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Further reading

    1. Cancer Biology
    Matthew Yorek, Xingshan Jiang ... Bing Li
    Research Article

    A high density of tumor-associated macrophages (TAMs) is associated with poorer prognosis and survival in breast cancer patients. Recent studies have shown that lipid accumulation in TAMs can promote tumor growth and metastasis in various models. However, the specific molecular mechanisms that drive lipid accumulation and tumor progression in TAMs remain largely unknown. Herein, we demonstrated that unsaturated fatty acids (FAs), unlike saturated ones, are more likely to form lipid droplets in murine macrophages. Specifically, unsaturated FAs, including linoleic acids (LA), activate the FABP4/CEBPα pathway, leading to triglyceride synthesis and lipid droplet formation. Furthermore, FABP4 enhances lipolysis and FA utilization by breast cancer cell lines, which promotes cancer cell migration in vitro and metastasis in vivo. Notably, a deficiency of FABP4 in murine macrophages significantly reduces LA-induced lipid metabolism. Therefore, our findings suggest FABP4 as a crucial lipid messenger that facilitates unsaturated FA-mediated lipid accumulation and lipolysis in TAMs, thus contributing to the metastasis of breast cancer.

    1. Cancer Biology
    2. Genetics and Genomics
    Rebecca Warfvinge, Linda Geironson Ulfsson ... Göran Karlsson
    Research Article

    The advent of tyrosine kinase inhibitors (TKIs) as treatment of chronic myeloid leukemia (CML) is a paradigm in molecularly targeted cancer therapy. Nonetheless, TKI-insensitive leukemia stem cells (LSCs) persist in most patients even after years of treatment and are imperative for disease progression as well as recurrence during treatment-free remission (TFR). Here, we have generated high-resolution single-cell multiomics maps from CML patients at diagnosis, retrospectively stratified by BCR::ABL1IS (%) following 12 months of TKI therapy. Simultaneous measurement of global gene expression profiles together with >40 surface markers from the same cells revealed that each patient harbored a unique composition of stem and progenitor cells at diagnosis. The patients with treatment failure after 12 months of therapy had a markedly higher abundance of molecularly defined primitive cells at diagnosis compared to the optimal responders. The multiomic feature landscape enabled visualization of the primitive fraction as a mixture of molecularly distinct BCR::ABL1+ LSCs and BCR::ABL1-hematopoietic stem cells (HSCs) in variable ratio across patients, and guided their prospective isolation by a combination of CD26 and CD35 cell surface markers. We for the first time show that BCR::ABL1+ LSCs and BCR::ABL1- HSCs can be distinctly separated as CD26+CD35- and CD26-CD35+, respectively. In addition, we found the ratio of LSC/HSC to be higher in patients with prospective treatment failure compared to optimal responders, at diagnosis as well as following 3 months of TKI therapy. Collectively, this data builds a framework for understanding therapy response and adapting treatment by devising strategies to extinguish or suppress TKI-insensitive LSCs.