Ravindran Menon Dinoop, Li Yang, Yamauchi Takeshi, Osborne Douglas Grant, Vaddi Prasanna Kumar, Wempe Michael F, Zhai Zili, Fujita Mayumi
Department of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Pharmaceuticals (Basel). 2021 Oct 26;14(11):1081. doi: 10.3390/ph14111081.
Over the last decade, therapies targeting immune checkpoints, such as programmed death-1 (PD-1), have revolutionized the field of cancer immunotherapy. However, low response rates and immune-related adverse events remain a major concern. Here, we report that epigallocatechin gallate (EGCG), the most abundant catechin in green tea, inhibits melanoma growth by modulating an immune response against tumors. In vitro experiments revealed that EGCG treatment inhibited interferon-gamma (IFN-γ)-induced PD-L1 and PD-L2 expression and JAK-STAT signaling. We confirmed that this effect was driven by inhibiting gene expression and STAT1 phosphorylation, thereby downregulating the PD-L1/PD-L2 transcriptional regulator IRF1 in both human and mouse melanoma cells. Animal studies revealed that the in vivo tumor-inhibitory effect of EGCG was through CD8+ T cells and that the inhibitory effect of EGCG was comparable to anti-PD-1 therapy. However, their mechanisms of action were different. Dissimilar to anti-PD-1 treatment that blocks PD-1/PD-L1 interaction, EGCG inhibited JAK/STAT signaling and PD-L1 expression in tumor cells, leading to the re-activation of T cells. In summary, we demonstrate that EGCG enhances anti-tumor immune responses by inhibiting JAK-STAT signaling in melanoma. EGCG could be used as an alternative treatment strategy to target the PD-L1/PD-L2-PD-1 axis in cancers.
在过去十年中，针对免疫检查点的疗法，如程序性死亡-1（PD-1），彻底改变了癌症免疫治疗领域。然而，低反应率和免疫相关不良事件仍然是一个主要问题。在此，我们报告表没食子儿茶素没食子酸酯（EGCG），绿茶中最丰富的儿茶素，通过调节针对肿瘤的免疫反应来抑制黑色素瘤生长。体外实验表明，EGCG处理可抑制干扰素-γ（IFN-γ）诱导的PD-L1和PD-L2表达以及JAK-STAT信号传导。我们证实这种效应是通过抑制基因表达和STAT1磷酸化来驱动的，从而在人和小鼠黑色素瘤细胞中下调PD-L1/PD-L2转录调节因子IRF1。动物研究表明，EGCG的体内肿瘤抑制作用是通过CD8 + T细胞实现的，并且EGCG的抑制作用与抗PD-1疗法相当。然而，它们的作用机制不同。与阻断PD-1/PD-L1相互作用的抗PD-1治疗不同，EGCG抑制肿瘤细胞中的JAK/STAT信号传导和PD-L1表达，导致T细胞重新激活。总之，我们证明EGCG通过抑制黑色素瘤中的JAK-STAT信号传导来增强抗肿瘤免疫反应。EGCG可作为一种替代治疗策略，用于靶向癌症中的PD-L1/PD-L2-PD-1轴。
