Engineered natural killer cells impede the immunometabolic CD73-adenosine axis in solid tumors

  1. Andrea Marie Chambers
  2. Kyle Byrnes Lupo
  3. Jiao Wang
  4. Jingming Cao
  5. Sagar Utturkar
  6. Nadia Atallah Lanman
  7. Victor Bernal-Crespo
  8. Shadia Jalal
  9. Sharon R Pine
  10. Sandra Toregrosa-Allen
  11. Bennett D Elzey
  12. Sandro Matosevic  Is a corresponding author
  1. Purdue University West Lafayette, United States
  2. Indiana University, United States
  3. Rutgers, The State University of New Jersey, United States

Abstract

Immunometabolic reprogramming due to adenosine produced by CD73 (encoded by the 5'-ectonucleotidase gene NT5E) is a recognized immunosuppressive mechanism contributing to immune evasion in solid tumors. Adenosine is not only known to contribute to tumor progression, but it has specific roles in driving dysfunction of immune cells, including natural killer (NK) cells. Here, we engineered human NK cells to directly target the CD73-adenosine axis by blocking the enzymatic activity of CD73. In doing so, the engineered NK cells not only impaired adenosinergic metabolism driven by the hypoxic uptake of ATP by cancer cells in a model of non-small-cell lung cancer, but also mediated killing of tumor cells due to the specific recognition of overexpressed CD73. This resulted in a 'single agent' immunotherapy that combines antibody specificity, blockade of purinergic signaling, and killing of targets mediated by NK cells. We also showed that CD73-targeted NK cells are potent in vivo and result in tumor arrest, while promoting NK cell infiltration into CD73+ tumors and enhancing intratumoral activation.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files, or are available at doi.org/10.5061/dryad.931zcrjnp. Source data have been provided for Figure 1 - Source Data 1 and 2 (Tables S1 and S2).

The following data sets were generated

Article and author information

Author details

  1. Andrea Marie Chambers

    Department of Industrial and Physical Pharmacy, Purdue University West Lafayette, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Kyle Byrnes Lupo

    Department of Industrial and Physical Pharmacy, Purdue University West Lafayette, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jiao Wang

    Department of Industrial and Physical Pharmacy, Purdue University West Lafayette, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jingming Cao

    Department of Industrial and Physical Pharmacy, Purdue University West Lafayette, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Sagar Utturkar

    Center for Cancer Research, Purdue University West Lafayette, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Nadia Atallah Lanman

    Center for Cancer Research, Purdue University West Lafayette, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Victor Bernal-Crespo

    Histology Research Laboratory, Purdue University West Lafayette, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Shadia Jalal

    Department of Medicine, Indiana University, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Sharon R Pine

    Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Sandra Toregrosa-Allen

    Center for Cancer Research, Purdue University West Lafayette, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Bennett D Elzey

    Center for Cancer Research, Purdue University West Lafayette, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Sandro Matosevic

    Department of Industrial and Physical Pharmacy, Purdue University West Lafayette, West Lafayette, United States
    For correspondence
    sandro@purdue.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5118-2455

Funding

V Foundation for Cancer Research (#D2019-039)

  • Sandro Matosevic

Lilly Graduate Fellowship (2019)

  • Andrea Marie Chambers

Walther Cancer Foundation (0186.01)

  • Sandro Matosevic

Migliaccio/Pfizer Graduate Fellowship (2019-2020)

  • Andrea Marie Chambers

National Cancer Institute (P30 CA023168)

  • Sagar Utturkar
  • Nadia Atallah Lanman
  • Sandra Toregrosa-Allen
  • Bennett D Elzey

National Cancer Institute (P30 CA082709)

  • Shadia Jalal

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of Purdue University (protocol 1112000342). All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering.

Human subjects: Written informed consent was obtained from all subjects involved in the study. All procedures performed in studies involving human participants were approved by Purdue University's Institutional Review Board (IRB). The peripheral blood NK cells were obtained from normal healthy donor volunteers who gave written consent through Purdue University's IRB protocol (#1804020540).

Copyright

© 2022, Chambers 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. Andrea Marie Chambers
  2. Kyle Byrnes Lupo
  3. Jiao Wang
  4. Jingming Cao
  5. Sagar Utturkar
  6. Nadia Atallah Lanman
  7. Victor Bernal-Crespo
  8. Shadia Jalal
  9. Sharon R Pine
  10. Sandra Toregrosa-Allen
  11. Bennett D Elzey
  12. Sandro Matosevic
(2022)
Engineered natural killer cells impede the immunometabolic CD73-adenosine axis in solid tumors
eLife 11:e73699.
https://doi.org/10.7554/eLife.73699

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https://doi.org/10.7554/eLife.73699

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