槐耳通过调节肿瘤免疫微环境提高抗 PD-L1Ab 治疗肝细胞癌的疗效。
Huaier improves the efficacy of anti-PD-L1 Ab in the treatment of hepatocellular carcinoma by regulating tumor immune microenvironment.
机构信息
Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China; Department of Integrated Traditional Chinese and Western Medicine, Cancer Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China.
Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
出版信息
Phytomedicine. 2024 Jan;123:155189. doi: 10.1016/j.phymed.2023.155189. Epub 2023 Nov 4.
BACKGROUND
Combination therapy is an effective method for augmenting the efficacy of immune checkpoint inhibitors (ICIs). Huaier is a commonly used Chinese patent medicine with substantial antitumor effects. The combination of Huaier and ICIs may increase the efficacy of ICIs against hepatocellular carcinoma (HCC).
METHODS
The major components of Huaier were detected by high-performance liquid chromatography-mass spectrometry. The optimal antitumor dose of Huaier was investigated in H22-bearing mice. Next, Huaier was combined with anti-CD8α antibody (Ab) or anti-PD-L1 Ab to observe the antitumor effect. The safety of these combination drugs was evaluated through blood biochemical tests and hematoxylin and eosin staining of histological sections. RT-qPCR, immunohistochemistry, flow cytometry, and transcriptome sequencing were performed to investigate the potential action mechanism of anti-PD-L1 Ab combined with Huaier against HCC.
RESULTS
HPLC-MS/MS identified 333 components of Huaier, including carboxylic acids and derivatives, thienothiophenes, phenols, flavonoids and so on. Huaier exhibited significant antitumor effects, with the strongest effect noted at a dose of 4 g/kg. Huaier boosted CD8 T cells infiltration into the tumor. Next, CD8 T cells were depleted by with anti-CD8α Ab, and the antitumor effect of Huaier was suppressed. Flow cytometry results revealed that CD8 T cells were reduced in the Huaier+anti-CD8α Ab group, with the antitumor effect of this group being inhibited. This indicated that CD8 T cells were key players in the antitumor activity of Huaier. Meanwhile, Huaier inhibited microvessel density (MVD), downregulated vascular endothelial growth factor A (VEGFA), and upregulated PD-L1 in tumor tissues. Finally, Huaier combined with anti-PD-L1 Ab exhibited a greater antitumor effect in the H22-bearing mice. And the results of liver and kidney function tests and histological section analysis unveiled that the safety of these drugs was excellent. According to the transcriptome sequencing results, Huaier combined with anti-PD-L1 Ab possibly exerted anti-HCC effects through immunomodulation, immune response, and so on.
CONCLUSIONS
Huaier exhibited a significant antitumor effect. It promoted CD8 T cells infiltration, upregulated PD-L1 expression, downregulated VEGFA expression, and inhibited MVD, thereby playing a significant antitumor immunoregulatory effect. The combination of Huaier and anti-PD-L1 Ab has significant antitumor effects, and this regimen has good safety. Therefore, Huaier combined with anti-PD-L1 Ab is a promising therapeutic approach against HCC.
背景
联合治疗是增强免疫检查点抑制剂（ICIs）疗效的有效方法。槐耳是一种具有显著抗肿瘤作用的常用中药。槐耳与 ICI 的联合应用可能会提高 ICI 对肝细胞癌（HCC）的疗效。
方法
采用高效液相色谱-质谱联用技术检测槐耳的主要成分。在 H22 荷瘤小鼠中考察槐耳的最佳抗肿瘤剂量。然后，将槐耳与抗 CD8α 抗体（Ab）或抗 PD-L1 Ab 联合使用，观察抗肿瘤效果。通过血液生化试验和组织学切片的苏木精-伊红染色评估这些联合药物的安全性。采用 RT-qPCR、免疫组织化学、流式细胞术和转录组测序等方法研究抗 PD-L1 Ab 联合槐耳治疗 HCC 的潜在作用机制。
结果
HPLC-MS/MS 鉴定出槐耳中的 333 种成分，包括羧酸及其衍生物、噻吩并噻吩、酚类、黄酮类等。槐耳表现出显著的抗肿瘤作用，在 4 g/kg 剂量下作用最强。槐耳促进 CD8 T 细胞浸润肿瘤。然后，用抗 CD8α Ab 耗尽 CD8 T 细胞，抑制槐耳的抗肿瘤作用。流式细胞术结果显示，槐耳+抗 CD8α Ab 组 CD8 T 细胞减少，该组抗肿瘤作用受到抑制。这表明 CD8 T 细胞是槐耳抗肿瘤活性的关键因素。同时，槐耳抑制肿瘤组织微血管密度（MVD），下调血管内皮生长因子 A（VEGFA），上调肿瘤组织 PD-L1。最后，槐耳联合抗 PD-L1 Ab 在 H22 荷瘤小鼠中表现出更强的抗肿瘤作用。肝肾功能试验和组织学切片分析结果表明，这些药物的安全性良好。根据转录组测序结果，槐耳联合抗 PD-L1 Ab 可能通过免疫调节、免疫应答等发挥抗 HCC 作用。
结论
槐耳具有显著的抗肿瘤作用。它促进 CD8 T 细胞浸润，上调 PD-L1 表达，下调 VEGFA 表达，抑制 MVD，从而发挥显著的抗肿瘤免疫调节作用。槐耳与抗 PD-L1 Ab 的联合应用具有显著的抗肿瘤效果，且安全性良好。因此，槐耳联合抗 PD-L1 Ab 是治疗 HCC 的一种有前途的方法。
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