Engineered natural killer cells impede the immunometabolic CD73-adenosine axis in solid tumors
- Purdue University West Lafayette, United States
- Indiana University, United States
- 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).
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Data from: Engineered natural killer cells impede the immunometabolic CD73-adenosine axis in solid tumorsDryad Digital Repository, doi:10.5061/dryad.931zcrjnp.
Article and author information
Author details
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.
Reviewing Editor
- Kerry Campbell, Fox Chase, United States
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).
Version history
- Received: September 7, 2021
- Preprint posted: October 5, 2021 (view preprint)
- Accepted: July 10, 2022
- Accepted Manuscript published: July 11, 2022 (version 1)
- Version of Record published: August 1, 2022 (version 2)
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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Engineered natural killer cells impede the immunometabolic CD73-adenosine axis in solid tumors
eLife 11:e73699.
https://doi.org/10.7554/eLife.73699
