Department of Hepatobiliary Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China.
Faculty of Hepato-Biliary-Pancreatic Surgery, The First Medical Center of Chinese People's Liberation, Army General Hospital, Beijing, 100039, China.
Cancer Immunol Immunother. 2024 Mar 2;73(4):62. doi: 10.1007/s00262-024-03652-2.
How to increase the response of immune checkpoint inhibitors (ICIs) is a challenge. In clinical, we found that Zoledronic acid (ZA) may increase the anti-tumor effect of immunotherapy for hepatocellular carcinoma (HCC). To explore the underlying mechanism, we established a mouse model of HCC by subcutaneously injecting Hepa1-6 cell line. The result showed that the tumor volume in the ZA plus anti-PD-1 monocloning antibody (anti-PD-1 mAb) treatment groups was significantly smaller than that of control group, and the onset time of tumor inhibition was even shorter than that of the anti-PD-1 mAb group. Using flow cytometry (FC) to detect the proportion of major immune cell subsets in tumor tissues of each group of mice, we found that the synergistic anti-tumor effect of ZA and anti-PD-1 mAb may be related to ZA-induced polarization of macrophages toward the M1 phenotype. Next, we performed bulk RNA sequencing on tumor samples from different groups to obtain differentially expressed genes (DEGs), which were then input DEGs into pathway enrichment analysis. Data indicated that ZA participated in the M1-type polarization via ferroptosis-related pathways. Our results revealed how ZA involves in the anti-tumor effect of PD-1 monoclonal antibody and provided a potential therapeutic candidate for patients with HCC.
如何提高免疫检查点抑制剂（ICIs）的应答率是一个挑战。在临床中，我们发现唑来膦酸（ZA）可能会增强免疫疗法治疗肝细胞癌（HCC）的抗肿瘤作用。为了探索其潜在机制，我们通过皮下注射 Hepa1-6 细胞系建立了 HCC 小鼠模型。结果表明，ZA 联合抗 PD-1 单克隆抗体（抗 PD-1 mAb）治疗组的肿瘤体积明显小于对照组，且肿瘤抑制的起始时间甚至短于抗 PD-1 mAb 组。通过流式细胞术（FC）检测各组小鼠肿瘤组织中主要免疫细胞亚群的比例，我们发现 ZA 和抗 PD-1 mAb 的协同抗肿瘤作用可能与 ZA 诱导的巨噬细胞向 M1 表型极化有关。接下来，我们对来自不同组的肿瘤样本进行了批量 RNA 测序，获得了差异表达基因（DEGs），然后将 DEGs 输入通路富集分析。数据表明，ZA 通过与铁死亡相关的途径参与 M1 型极化。我们的研究结果揭示了 ZA 如何参与 PD-1 单克隆抗体的抗肿瘤作用，并为 HCC 患者提供了一种潜在的治疗候选药物。
