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Functional expression of CD73 on human natural killer cells

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Abstract

The production of adenosine by CD73 on cancer cells in the tumor microenvironment is a recognized immunosuppressive mechanism contributing to immune evasion in many solid tumors. While NK cells have been purported to overexpress CD73 under certain conditions, this phenomenon has remained elusive and unclear. We have found that while NK cells are able to upregulate expression of CD73 on their surface when exposed to CD73+ cancer cells, this upregulation is not universal, nor is it often substantial. Rather, our data point to the extent of CD73 expression on NK cells to be both cancer-specific and environmentally-driven, and largely limited in intensity. We found that NK cell overexpression of CD73 responds to the level of CD73 on cancer cells and is enhanced in hypoxia. Interestingly, human CD73+ NK cells appear hyperfunctional in vitro compared to CD73− NK cells, suggesting that CD73 expression could be a bystander of NK cell activation. In addition, glioblastoma patient data show that tumor-infiltrating NK cells express CD73 variably, depending on donor, and present lower expression of CD16, alongside patient-specific changes in CEACAM1, CXCR3 and TIM-3, suggesting some functional changes in NK cell responses associated with expression of CD73 on NK cells in vivo. Taken together, our study is the first to show that while NK cells are largely resistant to the upregulation of CD73, CD73 expression is inducible on NK cells in response to CD73 on cancer cells, and these cells are associated with distinct functional signatures.

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Funding

The funding statement should be changed to: This work was supported by the V Foundation for Cancer Research (Grant #D2019-039), a Lilly Graduate Fellowship and a Migliaccio/Pfizer Graduate Fellowship to Andrea Chambers, and a McKeehan Graduate Fellowship to Kyle Lupo. The authors also gratefully acknowledge the support of the Biological Evaluation Shared Resource and the Flow Cytometry Shared Resource, with support from the Purdue Center for Cancer Research, NIH grant P30 CA023168, the IU Simon Cancer Center NIH grant P30 CA082709, and the Walther Cancer Foundation.

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Authors and Affiliations

  1. Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, IN, 47907, USA

    Andrea M. Chambers, Jiao Wang, Tram N. Dao, Kyle B. Lupo, Paige Veenhuis & Sandro Matosevic

  2. Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, 47907, USA

    Mitchell G. Ayers

  3. Enterprise Clinical Research Operations Biorepository, Indiana University Health, Indianapolis, IN, 46202, USA

    Veronika Slivova

  4. Department of Neurological Surgery, Indiana University, Indianapolis, IN, USA

    Aaron A. Cohen-Gadol

  5. Center for Cancer Research, Purdue University, West Lafayette, IN, 47907, USA

    Sandro Matosevic

Authors
  1. Andrea M. Chambers
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  2. Jiao Wang
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  3. Tram N. Dao
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  4. Kyle B. Lupo
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  5. Paige Veenhuis
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  6. Mitchell G. Ayers
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  7. Veronika Slivova
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  8. Aaron A. Cohen-Gadol
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  9. Sandro Matosevic
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Contributions

AMC and SM developed, planned the experiments, and wrote the manuscript. AMC developed the methodology, analyzed the data, and designed the figures. AMC, TND, JW, KBL, PV, and MGA performed experiments. VS and ACG provided patient samples. SM provided funding. All authors provided feedback and agreed to the published version of the manuscript.

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Correspondence to Sandro Matosevic.

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Chambers, A.M., Wang, J., Dao, T.N. et al. Functional expression of CD73 on human natural killer cells. Cancer Immunol Immunother 71, 3043–3056 (2022). https://doi.org/10.1007/s00262-022-03219-z

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  • DOI: https://doi.org/10.1007/s00262-022-03219-z

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