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CD73 immune checkpoint defines regulatory NK cells within the tumor microenvironment
- Source :
- Journal of Clinical Investigation. March, 2020, Vol. 130 Issue 3, p1185, 14 p.
- Publication Year :
- 2020
-
Abstract
- 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.sup.-]-positive NK cells than in [CD73.sup.-]-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 CD73positive NK cells undergo transcriptional reprogramming and upregulate IL-10 production via STAT3 transcriptional activity, suppressing CD4-positive T cell proliferation and IFN-[gamma] 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.<br />Introduction The CD73 metabolic immune checkpoint orchestrates a crucial homeostatic balance of extracellular adenosine levels as part of a negative feedback mechanism to control inflammatory responses within a stressed or [...]
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 130
- Issue :
- 3
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.618128123
- Full Text :
- https://doi.org/10.1172/JCI128895