GRHL2 suppression of NT5E/CD73 in breast cancer cells modulates CD73-mediated adenosine production and T cell recruitment
Bircan Coban,
Zi Wang,
Chen-yi Liao,
Klara Beslmüller,
Mieke A.M. Timmermans,
John W.M. Martens,
Jasmijn H.M. Hundscheid,
Bram Slutter,
Annelien J.M. Zweemer,
Elsa Neubert,
Erik H.J. Danen
Affiliations
Bircan Coban
Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands
Zi Wang
Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands; Department of clinical laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China
Chen-yi Liao
Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands
Klara Beslmüller
Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands
Mieke A.M. Timmermans
Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands
John W.M. Martens
Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands
Jasmijn H.M. Hundscheid
Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands
Bram Slutter
Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands
Annelien J.M. Zweemer
Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands
Elsa Neubert
Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands
Erik H.J. Danen
Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands; Corresponding author
Summary: Tumor tissues often contain high extracellular adenosine, promoting an immunosuppressed environment linked to mesenchymal transition and immune evasion. Here, we show that loss of the epithelial transcription factor, GRHL2, triggers NT5E/CD73 ecto-enzyme expression, augmenting the conversion of AMP to adenosine. GRHL2 binds an intronic NT5E sequence and is negatively correlated with NT5E/CD73 in breast cancer cell lines and patients. Remarkably, the increased adenosine levels triggered by GRHL2 depletion in MCF-7 breast cancer cells do not suppress but mildly increase CD8 T cell recruitment, a response mimicked by a stable adenosine analog but prevented by CD73 inhibition. Indeed, NT5E expression shows a positive rather than negative association with CD8 T cell infiltration in breast cancer patients. These findings reveal a GRHL2-regulated immune modulation mechanism in breast cancers and show that extracellular adenosine, besides its established role as a suppressor of T cell-mediated cytotoxicity, is associated with enhanced T cell recruitment.
