探討Laricitrin改善肺癌調控樹突細胞抑制機制及TWEAK於肺癌細胞之角色

Investigating the mechanism of laricitrin in ameliorating tumor-mediated dendritic cell suppression and the role of tumor necrosis factor‑like weak inducer of apoptosis in non‑small cell lung cancer

張維安(Wei-An Chang)

指導教授 ： 許雅玲

高雄醫學大學/醫學院/臨床醫學研究所博士班/博士(2020年)

摘要

葡萄及其種子的天然多酚化合物被認為是多種疾病的輔助治療劑，可能具有預防癌症的功能。此研究探討了葡萄酚類化合物調節癌症介導之免疫抑制能力。 西伯利亞落葉松黃酮(Laricitrin)可以改善肺
癌對樹突狀細胞（dentritic cells, DC）的抑制作用，其對於樹突細胞的分化，成熟度和功能都有影響。人類肺癌細胞株A549 和CL1-5 細胞可以使樹突細胞表現較高的IL-10 以及使初使T 細胞朝向第2 型免疫抑制反應細胞（Th2）轉化。在癌細胞的條件培養基中，西伯利亞落葉松黃酮會改善肺癌細胞樹突細胞分化和成熟的抑制並降低樹突細胞的IL-10 表達，並在體外和體內的實驗中將CD4+ T 細胞反應從Th2轉換為具有抗癌活性的Th1。西伯利亞落葉松黃酮反轉肺癌細胞對於樹突細胞失能作用是透過抑制信號轉導子和轉錄激活子3（STAT3）的磷酸化。西伯利亞落葉松黃酮也能夠增強順鉑(Cisplatin)在小鼠模型中的抗癌活性。因此，西伯利亞落葉松黃酮可能是一種有效的免疫佐劑且具有加強化療的效果。

關鍵字

樹突細胞 ； 西伯利亞落葉松黃酮 ； 肺癌 ； IL-10 ； STAT3

並列摘要

The natural polyphenolic compounds of grapes and their seeds are considered as adjuvants for the treatment of various diseases and may have the function of treating cancer. In this study, we investigated the ability of laricitrin, a grape phenolic compound, to regulate cancer-mediated immunosuppression. Laricitrin offers the greatest improvement in the inhibitory effect through dendritic cells on lung cancer. It affects their differentiation, maturity and function. Human lung cancer cell lines A549 and CL1-5 cells can make dendritic cells express higher IL-10 and transform T cells into type 2 immunosuppressive response cells (Th2). In the conditioned medium of cancer cells, laricitrin stimulated dendritic cell differentiation and maturation. Meanwhile, laricitrin can reduce the IL-10 expression of dendritic cells, and convert CD4+ T cell response from Th2 to Th1 in vitro and in vivo. Inhibiting the phosphorylation of signal transducers and transcription activator 3 (STAT3) can suppress the reversal effect of laricitrin on lung cancer-induced DCs’ paralysis. Laricitrin can also enhance the anti-cancer activity of cisplatin in mouse model. Therefore, Laricitrin may be an effective immune adjuvant with chemotherapy reinforcement.

並列關鍵字

IL-10 ； STAT3 ； dendritic cell ； laricitrin ； lung cancer

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