半夏脂溶性提取物通过恢复肿瘤相关树突状细胞的激活和成熟来增强抗肿瘤 T 细胞反应。
A lipid-soluble extract of Pinellia pedatisecta Schott enhances antitumor T cell responses by restoring tumor-associated dendritic cell activation and maturation.
机构信息
Department of Integration of Western and Traditional Medicine, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200090, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai, 200011, China.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
出版信息
J Ethnopharmacol. 2019 Sep 15;241:111980. doi: 10.1016/j.jep.2019.111980. Epub 2019 May 28.
ETHNOPHARMACOLOGICAL RELEVANCE
Pinellia pedatisecta Schott (PPS)is a traditional Chinese medicine functioning as reducing swelling and drying dampness. Pinellia pedatisecta Schott extract (PE) has been confirmed to suppress cervical tumor growth and modulate the antitumor CD4T helper immunity towards Th1.
AIMS
To explore the roles of PE in modulating tumor-associated dendritic cell (TADC) activation and function.
METHODS
For in vivo studies, HPVTC-1 mouse tumor models were conducted and treated with PE for 3 weeks (10 mg/kg/d or 20 mg/kg/day). The immune profiles of spleen, tumor-draining lymph nodes (TDLNs), tumor and serum were analyzed by flow cytometry and multiplexed bead-based immunoassay. For in vitro studies, TADCs were generated by tumor-conditioned medium and treated with PE solution. The maturation and function of TADCs were evaluated by flow cytometry, ELISA, mixed lymphocyte reaction (MLR) and cytotoxic T lymphocyte (CTL) assay. Furthermore, the effect of PE on SOCS1 pathway was examined by western blotting and real time PCR.
RESULTS
PE upregulated the expression of major histocompatibility complex class II (MHCII) and costimulatory molecules CD80 and CD86 on TADCs and promoted IL-12 secretion from TADCs. In addition, PE-treated TADCs promoted the proliferation of CD4 and CD8 T cells and induced the differentiation of IFN-γCD4 and GZMBCD8 T cells. PE-treated TADCs also elicited a more powerful antigen-specific cytotoxic T lymphocyte (CTL) response. Furthermore, PE treatment in vivo enhanced the proliferation, activated the functional ability (increased Ki67, CD137, GZMB or IFN-γ, TNF-α expression) and reversed the exhaustion (impaired CD95 or PD-1 expression) of antitumor T cells. Mechanistically, PE inhibited SOCS1-restrained JAK2 activation in TADCs.
CONCLUSIONS
PE efficiently restored the immature status of TADCs and enhanced their function as antigen-presenting cells to further elicit antitumor Th1 and CTL responses, suggesting that PE may be a potential immunomodulatory drug for cancer treatment.
民族药理学相关性
半夏（Pinellia pedatisecta Schott）是一种传统的中药，具有消肿除湿的作用。半夏提取物（PE）已被证实能抑制宫颈肿瘤的生长，并调节抗肿瘤的 CD4 辅助性 T 细胞免疫向 Th1 型免疫应答。
目的
探索 PE 调节肿瘤相关树突状细胞（TADC）激活和功能的作用机制。
方法
在体内研究中，采用 HPVTC-1 小鼠肿瘤模型，用 PE 处理 3 周（10mg/kg/d 或 20mg/kg/day）。通过流式细胞术和多指标微珠免疫分析检测脾、肿瘤引流淋巴结（TDLNs）、肿瘤和血清中的免疫谱。在体外研究中，用肿瘤条件培养基生成 TADCs，并用 PE 溶液处理。通过流式细胞术、ELISA、混合淋巴细胞反应（MLR）和细胞毒性 T 淋巴细胞（CTL）检测评估 TADCs 的成熟和功能。此外，通过 Western blot 和实时 PCR 检测 PE 对 SOCS1 通路的影响。
结果
PE 上调 TADCs 主要组织相容性复合体 II（MHCII）和共刺激分子 CD80 和 CD86 的表达，并促进 TADCs 分泌 IL-12。此外，PE 处理的 TADCs 促进 CD4 和 CD8 T 细胞的增殖，并诱导 IFN-γCD4 和 GZMBCD8 T 细胞的分化。PE 处理的 TADCs 还引发了更强大的抗原特异性 CTL 反应。此外，体内 PE 处理增强了增殖，激活了抗肿瘤 T 细胞的功能能力（增加 Ki67、CD137、GZMB 或 IFN-γ、TNF-α 的表达），并逆转了 T 细胞的耗竭（CD95 或 PD-1 的表达受损）。机制上，PE 抑制了 TADCs 中 SOCS1 抑制的 JAK2 激活。
结论
PE 有效地恢复了 TADCs 的未成熟状态，并增强了其作为抗原呈递细胞的功能，从而进一步引发抗肿瘤 Th1 和 CTL 反应，提示 PE 可能是一种有潜力的癌症治疗免疫调节药物。
Zotero 插件