Oroxylin a promoted apoptotic extracellular vesicles transfer of glycolytic kinases to remodel immune microenvironment in hepatocellular carcinoma model.
Oroxylin a promoted apoptotic extracellular vesicles transfer of glycolytic kinases to remodel immune microenvironment in hepatocellular carcinoma model.
复制标题
DOI：
10.1016/j.ejphar.2023.176037
复制
发表时间：
2023-09
影响因子：
5
通讯作者：
Peiwen Wang;Jie Cao;Zhi Feng;Yufang Tang;Xiaolei Han;Tianxiao Mao;Sichan Li;Qin Guo
中科院分区：
文献类型：
--
作者：
Peiwen Wang;Jie Cao;Zhi Feng;Yufang Tang;Xiaolei Han;Tianxiao Mao;Sichan Li;Qin Guo
尽管天然黄酮类化合物oroxylin A抑制了肝细胞癌的进展，但肿瘤微环境特别是癌细胞与免疫细胞之间的通讯是否受到其调节仍不清楚。本文研究了在体外条件下，由乳清素A诱导的癌细胞外囊泡对巨噬细胞的影响。数据显示，在HCC细胞中，通过半胱天冬酶-3介导的ROCK-1激活，其调节巨噬细胞的M1样极化，从而释放与肝硬化相关的细胞外囊泡。此外，在小鼠模型中，oroxylin A下调M2样巨噬细胞的群体并促进肿瘤微环境中的T细胞浸润，伴随着HCC发展的抑制和免疫检查点抑制剂治疗的增强。从机制上讲，来自HCC细胞的富含于由乳清素A引发的细胞外囊泡中的糖酵解蛋白被转移到巨噬细胞，在巨噬细胞中ROS依赖性NLRP 3炎性体被激活，因此有助于巨噬细胞的抗肿瘤表型。综上所述，本研究强调了在HCC模型中，oroxylin A促进肿瘤细胞和免疫细胞之间的代谢转移，有助于抑制肿瘤发展，并改善免疫治疗反应。
Although oroxylin A, a natural flavonoid compound, suppressed progression of hepatocellular carcinoma, whether the tumor microenvironment especially the communication between cancer cells and immune cells was under its modulation remained obscure. Here we investigated the effect of extracellular vesicles from cancer cells elicited by oroxylin A on macrophagesin vitro. The data shows oroxylin A elicits apoptosis-related extracellular vesicles through caspase-3-mediated activation of ROCK1in HCC cells, which regulates M1-like polarization of macrophage. Moreover, oroxylin A downregulates the population of M2-like macrophage and promotes T cells infiltration in tumor microenvironment, accompanied by suppression of HCC development and enhancement of immune checkpoint inhibitor treatment in mice model. Mechanistically, glycolytic proteins enriched in oroxylin A-elicited extracellular vesicles from HCC cells are transferred to macrophages where ROS-dependent NLRP3 inflammasome is activated, therefore contributing to anti-tumor phenotype of macrophage. Taken together, this study highlights that oroxylin A promotes metabolic shifts between tumor cells and immune cells, facilitates to inhibit tumor development, and improves immunotherapy response in HCC model.