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).
-
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.
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.
Metrics
-
- 1,948
- views
-
- 476
- downloads
-
- 19
- 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)
Engineered natural killer cells impede the immunometabolic CD73-adenosine axis in solid tumors
eLife 11:e73699.
https://doi.org/10.7554/eLife.73699
Further reading
-
- Immunology and Inflammation
The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) has been increasing worldwide. Since gut-derived bacterial lipopolysaccharides (LPS) can travel via the portal vein to the liver and play an important role in producing hepatic pathology, it seemed possible that (1) LPS stimulates hepatic cells to accumulate lipid, and (2) inactivating LPS can be preventive. Acyloxyacyl hydrolase (AOAH), the eukaryotic lipase that inactivates LPS and oxidized phospholipids, is produced in the intestine, liver, and other organs. We fed mice either normal chow or a high-fat diet for 28 weeks and found that Aoah-/- mice accumulated more hepatic lipid than did Aoah+/+ mice. In young mice, before increased hepatic fat accumulation was observed, Aoah-/- mouse livers increased their abundance of sterol regulatory element-binding protein 1, and the expression of its target genes that promote fatty acid synthesis. Aoah-/- mice also increased hepatic expression of Cd36 and Fabp3, which mediate fatty acid uptake, and decreased expression of fatty acid-oxidation-related genes Acot2 and Ppara. Our results provide evidence that increasing AOAH abundance in the gut, bloodstream, and/or liver may be an effective strategy for preventing or treating MASLD.
-
- Immunology and Inflammation
- Microbiology and Infectious Disease
Pseudomonas aeruginosa (PA) is an opportunistic, frequently multidrug-resistant pathogen that can cause severe infections in hospitalized patients. Antibodies against the PA virulence factor, PcrV, protect from death and disease in a variety of animal models. However, clinical trials of PcrV-binding antibody-based products have thus far failed to demonstrate benefit. Prior candidates were derivations of antibodies identified using protein-immunized animal systems and required extensive engineering to optimize binding and/or reduce immunogenicity. Of note, PA infections are common in people with cystic fibrosis (pwCF), who are generally believed to mount normal adaptive immune responses. Here, we utilized a tetramer reagent to detect and isolate PcrV-specific B cells in pwCF and, via single-cell sorting and paired-chain sequencing, identified the B cell receptor (BCR) variable region sequences that confer PcrV-specificity. We derived multiple high affinity anti-PcrV monoclonal antibodies (mAbs) from PcrV-specific B cells across three donors, including mAbs that exhibit potent anti-PA activity in a murine pneumonia model. This robust strategy for mAb discovery expands what is known about PA-specific B cells in pwCF and yields novel mAbs with potential for future clinical use.
