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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-y 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.
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 damaged tissue microenvironment (1). The lack of CD73 expression could implicate physiological wound healing and immunomodulation within the tissue microenvironment (2). Within the tumor microenvironment (TME), however, metabolic stress accumulates along with tumor progression, which leads to a dysregulated expression and activity of CD73 in cancers including breast cancer, metastatic melanoma, and ovarian cancer (3-6). Overexpression of CD73 within a tumor not only contributes to metastasis and anthracycline resistance, but also to immune evasion due to dysregulation of adenosine production (6, 7). For these reasons, inhibitors of CD73 are today used in cancer immunotherapy in combination with existing cancer treatments including anti-PD-1/anti-PD-L1 therapy (1, 8-11).
Tumor progression on immune checkpoint therapy can be associated with defects in tumor antigen presentation, which results in lack of tumor cell recognition by T cells (12). This has inspired the development of therapies based on activating natural killer (NK) cells (13). NK...