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Adenosine increases PD-L1 expression in mesenchymal stromal cells derived from cervical cancer through its interaction with A 2A R/A 2B R and the production of TGF-β1.

Luis Antonio Marín-AquinoMaría de Lourdes Mora-GarcíaMoreno-Lafont MarthaRosario García-RochaJuan José MontesinosRubén López-SantiagoLuvia Enid Sánchez-TorresDaniela Berenice Torres-PinedaBenny Weiss-SteiderJorge Hernández-MontesChristian Azucena Don-LópezAlberto Monroy-García
Published in: Cell biochemistry and function (2024)
Mesenchymal stromal cells (MSCs) together with malignant cells present in the tumor microenvironment (TME), participate in the suppression of the antitumor immune response through the production of immunosuppressive factors, such as transforming growth factor beta 1 (TGF-β1). In previous studies, we reported that adenosine (Ado), generated by the adenosinergic activity of cervical cancer (CeCa) cells, induces the production of TGF-β1 by interacting with A 2A R/A 2B R. In the present study, we provide evidence that Ado induces the production of TGF-β1 in MSCs derived from CeCa tumors (CeCa-MSCs) by interacting with both receptors and that TGF-β1 acts in an autocrine manner to induce the expression of programmed death ligand 1 (PD-L1) in CeCa-MSCs, resulting in an increase in their immunosuppressive capacity on activated CD8+ T lymphocytes. The addition of the antagonists ZM241385 and MRS1754, specific for A 2A R and A 2B R, respectively, or SB-505124, a selective TGF-β1 receptor inhibitor, in CeCa-MSC cultures significantly inhibited the expression of PD-L1. Compared with CeCa-MSCs, MSCs derived from normal cervical tissue (NCx-MSCs), used as a control and induced with Ado to express PD-L1, showed a lower response to TGF-β1 to increase PD-L1 expression. Those results strongly suggest the presence of a feedback mechanism among the adenosinergic pathway, the production of TGF-β1, and the induction of PD-L1 in CeCa-MSCs to suppress the antitumor response of CD8+ T lymphocytes. The findings of this study suggest that this pathway may have clinical importance as a therapeutic target.
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