Search

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 A2AR/A2BR. 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 A2AR and A2BR, 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. Significance statement: This study provides the first evidence that Ado, when interacting with A2AR or A2BR in CeCa‐MSCs, induces the production of TGF‐β1 and PD‐L1 expression through autocrine action, resulting in an increase in the immunosuppressive capacity of CeCa‐MSCs on activated CD8+ T lymphocytes. [ABSTRACT FROM AUTHOR]

The present study provides evidence showing that adenosine (Ado) increases the expression of programmed death ligand 1 (PD-L1) in cervical cancer (CeCa) cells by interacting with A2AR/A2BR and that TGF-β1 acts in an autocrine manner to induce PD-L1 expression, enhancing the immunosuppressive effects of CeCa cells on activated T lymphocytes (ATLs) and CD8+ cytotoxic T lymphocytes (CTLs) specific for antigenic peptides derived from E6 and E7 proteins of HPV-16. Interestingly, the addition of the antagonists ZM241385 and MRS1754, which are specific for A2AR and A2BR, respectively, or SB-505124, which is a selective TGF-β1 receptor inhibitor, to CeCa cell cultures significantly inhibited PD-L1 expression. In addition, supernatants from CeCa cells that were treated with Ado (CeCa-Ado Sup) increased the expression of PD-1, TGF-β1, and IL-10 and decreased the expression of IFN-γ in ATLs. Interestingly, the addition of an anti-TGF-β neutralizing antibody strongly reversed the effect of CeCa-Ado Sup on PD-1 expression in ATLs. These results strongly suggest the presence of a feedback mechanism that involves the adenosinergic pathway, the production of TGF-β1, and the upregulation of PD-L1 expression in CeCa cells that suppresses the antitumor response of CTLs. The findings of this study suggest that this pathway may be clinically important and may be a therapeutic target. [ABSTRACT FROM AUTHOR]

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., (© 2024 The Authors. Cell Biochemistry and Function published by John Wiley & Sons Ltd.)

Cervical cancer (CeCa) produces large amounts of IL-10, which downregulates the major histocompatibility complex class I molecules (HLA-I) in cancer cells and inhibits the immune response mediated by cytotoxic T lymphocytes (CTLs). In this study, we analyzed the ability of CeCa cells to produce IL-10 through the CD73-adenosine pathway and its effect on the downregulation of HLA-I molecules to evade CTL-mediated immune recognition. CeCa cells cultured in the presence of ≥10 µM AMP or adenosine produced 4.5-6 times as much IL-10 as unstimulated cells. The silencing of CD73 or the blocking of A 2B R with the specific antagonist MRS1754 reversed this effect. In addition, IL-10 decreased the expression of HLA-I molecules, resulting in the protection of CeCa cells against the cytotoxic activity of CTLs. The addition of MRS1754 or anti-IL-10 reversed the decrease in HLA-I molecules and favored the cytotoxic activity of CTLs. These results strongly suggest the presence of a feedback loop encompassing the adenosinergic pathway, the production of IL-10, and the downregulation of HLA-I molecules in CeCa cells that favors immune evasion and thus tumor progression. This pathway may have clinical importance as a therapeutic target., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Ltd.)