腺苷酸
间充质干细胞
自分泌信号
间质细胞
癌症研究
转化生长因子
免疫系统
CD8型
肿瘤微环境
腺苷
内皮糖蛋白
转化生长因子β
受体
化学
腺苷受体
细胞生物学
生物
免疫学
内分泌学
生物化学
干细胞
川地34
兴奋剂
作者
Luis Antonio Marín‐Aquino,María de Lourdes Mora‐García,Martha C. Moreno‐Lafont,Rosario García‐Rocha,Juan José Montesinos,Rubén López‐Santiago,Luvia Enid Sánchez‐Torres,Daniela Berenice Torres‐Pineda,Benny Weiss‐Steider,Jorge Hernández‐Montes,Christian Azucena Don‐López,Alberto Monroy‐García
摘要
Abstract 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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