PLX265346

GSE125119: CD73 Immune Checkpoint Defines Inducible Regulatory NK cells in the Tumor Microenvironment

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

High levels of ecto-5'-nucleotidase (CD73) have been implicated in immune suppression and tumor progression. Elevated levels of CD73 has also been observed in patients who progress on antiPD-1 immunotherapy. While regulatory T cells can express CD73 and inhibit T cell responses via the production of adenosine, less is known if conventional T cells and natural killer (NK) cells can express CD73. We found that the expression of CD73 is restricted to tumor-infiltrating NK cells and the frequency of these cells correlate with larger tumor size in patients with breast cancer. In addition, the expression of other immune checkpoint receptors including LAG-3 and VISTA was significantly higher in CD73 positive NK cells than on CD73 negative NK cells. Furthermore, the prognostic value of CD73 gene expression was influenced by NK cell signature expressed in patients with breast cancer and sarcoma. Mechanistically, upon engagement of 4-1BBL on tumor cells, NK cells transport CD73 in intracellular vesicles to the cell surface and extracellular space via actin polymerization-dependent exocytosis. These CD73 positive NK cells undergo transcriptional reprogramming and upregulate IL10 production via STAT3 transcriptional activity and suppress CD4 T cell activity. Altogether, 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. SOURCE: Andreas Lundqvist (andreas.lundqvist@ki.se) - Karolinska Institutet