CD73 immune checkpoint defines regulatory NK cells within the tumor microenvironment

J Clin Invest. 2020 Mar 2;130(3):1185-1198. doi: 10.1172/JCI128895.


High levels of ecto-5'-nucleotidase (CD73) have been implicated in immune suppression and tumor progression, and have also been observed in cancer patients who progress on anti-PD-1 immunotherapy. Although regulatory T cells can express CD73 and inhibit T cell responses via the production of adenosine, less is known about CD73 expression in other immune cell populations. We found that tumor-infiltrating NK cells upregulate CD73 expression and the frequency of these CD73-positive NK cells correlated with larger tumor size in breast cancer patients. In addition, the expression of multiple alternative immune checkpoint receptors including LAG-3, VISTA, PD-1, and PD-L1 was significantly higher in CD73-positive NK cells than in CD73-negative NK cells. Mechanistically, NK cells transport CD73 in intracellular vesicles to the cell surface and the extracellular space via actin polymerization-dependent exocytosis upon engagement of 4-1BBL on tumor cells. These CD73-positive NK cells undergo transcriptional reprogramming and upregulate IL-10 production via STAT3 transcriptional activity, suppressing CD4-positive T cell proliferation and IFN-γ production. Taken together, our results support the notion that tumors can hijack NK cells as a means to escape immunity and that CD73 expression defines an inducible population of NK cells with immunoregulatory properties within the tumor microenvironment.

Keywords: Immunology; NK cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-1BB Ligand / immunology
  • 5'-Nucleotidase / immunology*
  • GPI-Linked Proteins / immunology
  • Humans
  • K562 Cells
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / pathology
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Lymphocytes, Tumor-Infiltrating / pathology
  • Neoplasm Proteins / immunology*
  • Neoplasms / immunology*
  • Neoplasms / pathology
  • Tumor Escape*
  • Tumor Microenvironment / immunology*


  • 4-1BB Ligand
  • GPI-Linked Proteins
  • Neoplasm Proteins
  • 5'-Nucleotidase
  • NT5E protein, human

Grant support

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