A lipid-soluble extract of Pinellia pedatisecta Schott orchestrates intratumoral dendritic cell-driven immune activation through SOCS1 signaling in cervical cancer
A lipid-soluble extract of Pinellia pedatisecta Schott orchestrates intratumoral dendritic cell-driven immune activation through SOCS1 signaling in cervical cancer
复制标题
半夏 Schott 的脂溶性提取物通过 SOCS1 信号传导在宫颈癌中协调瘤内树突状细胞驱动的免疫激活
DOI：
10.1016/j.jep.2020.112837
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发表时间：
2021
影响因子：
5.4
通讯作者：
Li Guiling
中科院分区：
文献类型：
--
作者：
Wang Yumeng;Lu Chong;Huang Haixia;Yao Sheng;Xu Congjian;Ye Yang;Gui Suiqi;Li Guiling
民族药理学相关性掌叶半夏提取物（PE）是从传统的中国药用植物掌叶半夏中提取的。PE抑制宫颈肿瘤的生长，并表现出对树突状细胞（DCs）的影响，导致抗肿瘤的CD 4+和CD 8 +responses.AimsTo探讨潜在的机制，PE调制肿瘤相关的树突状细胞（TADC）的激活和function.MethodsDCs和TADC从小鼠骨髓中产生，并暴露于PE溶液在不同剂量，以及重复剂量在不同的时间间隔分开。采用定量PCR、Western blot、流式细胞术和基因沉默等方法分析PE对SOCS 1/JAK 2/STAT信号通路的调节作用。此外，我们还分离了人宫颈肿瘤浸润DC（TIDC），并进行了体外刺激模型，以观察PE的影响。对于培养的DCs andex vivohuman标本的表型分析，我们使用流式细胞术检测与细胞function.ResultsIn培养的TADCs和人宫颈TIDCs，成熟和功能标记（MHC II，CD 80，CD 83，CD 86和IL-12）下调，而SOCS 1上调的分子标记。PE增强宫颈TIDCs中CD 80、CD 86和IL-12的表达，从而诱导CTL中CD 107 a、GZMB和穿孔素的表达增加，并且进一步诱导大量肿瘤细胞的凋亡。在培养的TADCs中，PE以剂量和时间依赖性方式下调SOCS 1表达并激活JAK 2、STAT 1、STAT 4和STAT 5的磷酸化。SOCS 1沉默后PE上调TADCs上MHCII、CD 80、CD 86、IL-12的作用被阻断。结论在这项研究中，PE恢复了宫颈TIDCs受损的功能，从而引发进一步的抗肿瘤CTL应答。PE对TADCs的作用是通过抑制SOCS 1和激活下游JAK 2-STAT 1/STAT 4/STAT 5通路介导的。PE可能通过阻断DC中SOCS 1信号通路而成为一种有效的抗肿瘤免疫调节药物。
Ethnopharmacological relevancePinellia pedatisecta Schott extract (PE) is generated from Pinellia pedatisecta Schott, a traditional Chinese medicinal plant. PE suppresses cervical tumor growth and exhibits effects on dendritic cells (DCs) that lead to modulation of antitumor CD4+and CD8+responses.AimsTo explore the underlying mechanisms by which PE modulates tumor-associated dendritic cell (TADC) activation and function.MethodsDCs and TADCs were generated from murine bone marrow and exposed to PE solutions at different doses, as well as to repeated doses separated at different time intervals. Quantitative PCR, Western blot analysis, flow cytometry, and gene silencing were used to analyze the modulatory effects of PE on the SOCS1/JAK2/STAT pathways. Furthermore, we separated human cervical tumor-infiltrated DCs (TIDCs) and conducted anex-vivostimulation model to observe the effect of PE. For phenotypic analysis of cultured DCs andex vivohuman specimens, we used flow cytometry to detect the molecular markers associated with cell function.ResultsIn cultured TADCs and human cervical TIDCs, maturation- and functional markers (MHCII, CD80, CD83, CD86, and IL-12) were downregulated, whereas SOCS1 was upregulated. PE enhanced the expression of CD80, CD86, and IL-12 in cervical TIDCs, which induced increased expression of CD107a, GZMB, and perforin in CTLs, and furthermore induced apoptosis in a larger number of tumor cells. In cultured TADCs, PE downregulated SOCS1 expression and activated the phosphorylation of JAK2, STAT1, STAT4, and STAT5 in both dose- and time-dependent manners. The effects of PE upregulating MHCII, CD80, CD86, IL-12 on TADCs were blocked after SOCS1 silencing.ConclusionsIn this study, PE restored the impaired function of cervical TIDCs, thereby eliciting further antitumor CTL responses. The effects of PE on TADCs were mediated through inhibition of SOCS1 and activation of downstream JAK2-STAT1/STAT4/STAT5 pathways. PE may be a potent and effective immunomodulatory drug for antitumor treatment via the blockade of SOCS1 signaling in DCs.