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. While 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+ 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 IL10 production via STAT3 transcriptional activity, suppressing CD4 T cell proliferation and IFN-ɣ production. Taken together, our results support that tumors can hijack NK cells as a means to escape immunity and that CD73 expression defines an inducible population of NK cells with immune regulatory properties within the tumor microenvironment.
Shi Yong Neo, Ying Yang, Record Julien, Ran Ma, Xinsong Chen, Ziqing Chen, Nicholas P. Tobin, Emily Blake, Christina Seitz, Ron Thomas, Arnika Kathleen Wagner, John Andersson, Jana de Boniface, Jonas Bergh, Shannon Murray, Evren Alici, Richard Childs, Martin Johansson, Lisa S. Westerberg, Felix Haglund, Johan Hartman, Andreas Lundqvist
Guidelines: The Editorial Board will only consider letters that we deem relevant and of interest to our readers. We will not post data that have not been subjected to peer review, nor will we post letters that are essentially a reiteration of another letter. All accepted letters will be posted on our website within one week of acceptance. We reserve the right to edit any letter for length, content, and clarity. Authors of all accepted letters will be asked to preview any changes. Authors will be notified by e-mail if their letters were not accepted. As this is a final decision, no appeals will be considered.
Specific requirements: All letters must be 400 words or fewer. You may enter the letter as plain text or HTML. The author's name and e-mail address are required, and will be posted with the letter. All possible conflicts of interest must be noted, even if they are not posted. If you wish to include a figure (keep in mind that non-peer-reviewed data will not be posted), please contact the editors directly at firstname.lastname@example.org.