Jianpi Huayu Decoction Attenuates the Immunosuppressive Status of H22 Hepatocellular Carcinoma-Bearing Mice: By Targeting Myeloid-Derived Suppressor Cells
Jianpi Huayu Decoction Attenuates the Immunosuppressive Status of H22 Hepatocellular Carcinoma-Bearing Mice: By Targeting Myeloid-Derived Suppressor Cells
复制标题
健脾化瘀汤通过靶向骨髓源性抑制细胞减轻 H-22 肝细胞癌小鼠的免疫抑制状态
DOI：
10.3389/fphar.2020.00016
复制
发表时间：
2020-02-18
影响因子：
5.6
通讯作者：
Wang, Changjun
中科院分区：
文献类型：
--
作者：
Xie, Yingjie;Zhang, Yuan;Wang, Changjun
髓源性抑制细胞（MDSCs）在肿瘤诱导的免疫抑制微环境中起着重要作用，目前仍是肿瘤有效治疗的一个障碍。诱导MDSCs成熟被证实是减轻荷瘤宿主免疫抑制的有效方法。中药具有减轻肿瘤患者免疫抑制和低毒性的特点。健脾化瘀汤是基于中医理论和临床实践的经验丰富的治疗肿瘤的中药方剂。我们之前观察到JHD降低了肿瘤中白细胞介素-10 （IL-10）和转化生长因子β (tgf - β)的表达。发现IL-10和tgf - β是与MDSCs诱导的免疫抑制正相关的细胞因子。本研究旨在进一步探讨JHD对H-22肝癌小鼠模型免疫系统的调节作用。主要采用流式细胞术检测免疫细胞比例，分析MDSCs的凋亡、分化和活性氧。我们发现，JHD显著降低了脾脏结构的破坏，降低了调节性T细胞（Treg）和T辅助17细胞（Th17）的比例，增加了脾脏细胞毒性T淋巴细胞（CTL）、树突状细胞（DC）和CD11b(+)Gr-1（+）细胞的比例，但T辅助1细胞（Th1）、T辅助2细胞（Th2）和巨噬细胞的比例无显著变化。体外实验显示，随着JHD刺激时间的延长，MDSCs的凋亡减少，这部分解释了脾脏中CD11b(+)Gr-1（+）细胞的增加。同时，JHD在体外可促进MDSCs向巨噬细胞和树突状细胞分化，减弱MDSCs中ROS的表达，降低其对CD4(+) T细胞增殖的抑制作用。因此，当这些药物抑制了CD11b(+)Gr-1（+）细胞的免疫抑制能力，同时促进其成熟并补充树突状细胞时，荷瘤宿主脾脏中CD11b(+)Gr-1（+）细胞比例的增加可能并不是坏事。一般来说，JHD可能是一种补充和替代药物，可以减轻肝细胞癌诱导的免疫抑制状态，可能通过促进分化和抑制MDSCs的免疫抑制活性来实现。
Tumor-induced immunosuppressive microenvironment in which myeloid-derived suppressor cells (MDSCs) plays an important role, remains an obstacle for effective oncotherapy currently. Inducing MDSCs into maturation was confirmed as an effective method to reduce the tumor-bearing host's immunosuppression. Traditional Chinese medicines (TCM) possess characteristics of alleviating immunosuppression of cancer patients and low toxicity. Jianpi Huayu Decoction (JHD) was an experienced formula of TCM for oncotherapy based on TCM theory and clinical practice. We previously observed that JHD attenuated the expression of interleukin-10 (IL-10) and transforming growth factor beta (TGF-beta) in tumor. IL-10 and TGF-beta were found to be cytokines positively related to immunosuppression induced by MDSCs. Here, our study was designed to further investigate the regulation of JHD on the immune system in the H-22 liver-cancer mouse model. Mainly, flow cytometry was used to detect the proportion of immune cells, to analyze the apoptosis, differentiation and reactive oxygen species of MDSCs. We found that JHD significantly reduced the destruction of spleen structure, reduced the proportion of regulatory T cells (Treg) and T helper 17 cells (Th17), and increased the proportion of cytotoxic T lymphotes (CTL), Dendritic cells (DC) and CD11b(+)Gr-1(+)cells in spleen, but with no significant change of T helper 1 cells (Th1), T helper 2 cells (Th2) and macrophages. In vitro experiments showed that apoptosis of MDSCs was decreased as the time of JHD stimulation increased, which partly explained the increase of CD11b(+)Gr-1(+)cells in the spleen. Meanwhile, JHD could promote the differentiation of MDSCs into macrophages and dendritic cells, attenuate expression of ROS in MDSCs and reduce its inhibition on the proliferation of CD4(+) T cells, in vitro. Therefore, that the proportion of CD11b(+)Gr-1(+) cells increased in the spleen of tumor-bearing hosts may not be villainy after treatment, when these drugs suppress the immunosuppressive ability of CD11b(+)Gr-1(+) cells and promote it mature to replenish dendritic cell, at the same time. Generally, JHD may be a complementary and alternative drug for attenuating the immunosuppressive status induced by hepatocellular carcinoma, possibly by promoting differentiation and inhibiting the immunosuppressive activity of MDSCs.