期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 920, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.ejphar.2022.174822
关键词
ATRA; PD-L1; PD-L1 antibody; JAK-STAT pathway; GC
资金
- National Natural Science Foundation of China [U2004101, U21A20416]
This study investigates the mechanism of all-trans retinoic acid (ATRA)-induced PD-L1 expression in gastric cancer cells and the impact of ATRA on cancer-associated immune suppression. The study reveals that ATRA enhances PD-L1 expression by increasing its protein stability and synthesis, which can be suppressed by the JAK pan-inhibitor ruxolitinib (RUX). Additionally, the upregulation of PD-L1 induced by ATRA renders gastric cancer cells resistant to T-cell killing, and blocking PD-L1 expression can inhibit tumor growth.
The vitamin A metabolite all-trans retinoic acid (ATRA) plays a key role in immune response, but effects of ATRA on cancer-associated immunity remains unclear. Previously, we have shown that ATRA regulates the expression of PD-L1 in gastric cancer (GC) cells. We herein reported the mechanism underlying ATRA-induced PD-L1 expression in GC cells and the effects of ATRA on cancer-associated immunosuppression in vitro and in vivo. ATRA enhanced PD-L1 expression through increasing its protein stability and protein synthesis, which was suppressed by JAK pan-inhibitor ruxolitinib (RUX) but enhanced in the combination with IFN-gamma. In T-cell-mediated killing assay, the upregulation of PD-L1-induced by ATRA rendered GC cells strongly resistant to activated T-cell killing, which was reversed by RUX. In vivo, PD-L1 antibody restricted tumor growth, but ATRA antagonized PD-L1 antibody efficacy. Importantly, RUX not only inhibited the expression of PD-L1 induced by ATRA, but also resensitized GC cells to PD-L1 antibody. In conclusion, our study illustrated that ATRA attenuated the effect of PD-L1 blockade through upregulating PD-L1 and blocking PD-L1 expression is an important role for the generation of effective anti-tumor immune response in the combination of immunotherapy and chemotherapy or targeted therapy.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据