Sorafenib attenuated the function of natural killer cells infiltrated in HCC through inhibiting ERK1/2
Sorafenib attenuated the function of natural killer cells infiltrated in HCC through inhibiting ERK1/2
复制标题
索拉非尼通过抑制 ERK1/2 减弱 HCC 中浸润的自然杀伤细胞的功能
DOI：
10.1016/j.intimp.2019.105855
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发表时间：
2019-11-01
影响因子：
5.6
通讯作者：
Wang, Junjie
中科院分区：
文献类型：
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作者：
Li, Chunxiao;Wei, Shuhua;Wang, Junjie
索拉非尼已被广泛应用于晚期肝细胞癌（HCC）的治疗。自然杀伤细胞（Natural Killer cells，NK）是一种重要的细胞毒性天然淋巴细胞，在肝脏和肿瘤中发挥重要的效应功能。然而，索拉非尼如何影响NK的功能仍有待阐明。在此，我们利用小鼠肝癌细胞系hepa 1-6皮下和原位荷瘤小鼠。在终点时，使用FACS、ELISA、WB等探索血液、肝脏、TDLN和肿瘤中的NK的数量和功能。为了证实索拉非尼对NK的直接作用，使用FACS分选NK，然后用索拉非尼刺激NK，使用qPCR、western blot和体外FACS检测功能和相关机制。最后，我们发现索拉非尼导致肿瘤进展的显著阻断，但通过抑制NK细胞的增殖来减少NK细胞的数量。这一表型使我们对NK细胞的终末功能进行了研究，揭示了索拉非尼B可以减少效应分子和细胞因子的产生，如穿孔素、颗粒酶B、TNF-α、IFN-γ等。此外，索拉非尼B处理后，NK细胞中的p-ERK 1/2被抑制，使用ERK 1/2抑制剂也可以获得类似的NK细胞趋势。总的来说，我们的数据表明，索拉非尼作为一种关键的抑制剂，通过抑制ERK 1/2来控制NK细胞的数量和功能。
Sorafenib has been systemically utilized to therapy the advanced hepatocellular carcinoma (HCC). Natural killer cells (NKs) are important cytotoxic innate lymphocytes, which can exert effector functions especially in liver and tumor. However, how Sorafenib affects the function of NKs remains to be elucidated. Here, we utilized the subcutaneous and in situ tumor bearing mice with mouse hepatoma cell line hepa 1-6. At the endpoint, the number and function of NKs in blood, liver, TDLN, and tumor were explored using FACS, ELISA, WB, etc. To confirm the direct effects of Sorafenib on NKs, the NKs were sorted using FACS, which were then stimulated with Sorafenib to detect the functions and the relevant mechanisms using qPCR, western blot, and FACS in vitro. Finally, we found that Sorafenib led to a significant block of tumor progression, but reduced the number of NK cells through suppressing the proliferation of NK cells. This phenotype made us study the terminal function of NK cells, revealing that Sorafenib could decrease the production of effector molecules and cytokines, such as perforin, granzyme B, TNF-alpha, IFN-gamma, etc. Besides, p-ERK1/2 in NK cells was inhibited after treatment with Sorafenib, and a similar tendency of NK cells could be achieved using ERK1/2 inhibitor. Collectively, our data suggested that Sorafenib functioned as a critical inhibitor that controlled the number and function of NK cells through inhibiting ERK1/2.