Wang Pei, Xu Ming-Hao, Xu Wen-Xin, Dong Zi-Ying, Shen Ying-Hao, Qin Wen-Zheng
Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China.
Department of Digestive Medicine, Wuwei People's Hospital, Wuwei City, Gansu Province, 733000, People's Republic of China.
J Hepatocell Carcinoma. 2024 May 8;11:787-800. doi: 10.2147/JHC.S450468. eCollection 2024.
Anti-programmed death-1 (PD1) antibodies have changed the treatment landscape for hepatocellular carcinoma (HCC) and exhibit promising treatment efficacy. However, the majority of HCCs still do not respond to anti-PD-1 therapy.
We analyzed the expression of CXCL9 in blood samples from patients who received anti-PD-1 therapy and evaluated its correlation with clinicopathological characteristics and treatment outcomes. Based on the results of Cox regression analysis, a nomogram was established for predicting HCC response to anti-PD-1 therapy. qRT‒PCR and multiple immunofluorescence assays were utilized to analyze the proportions of N1-type neutrophils in vitro and in tumor samples, respectively.
The nomogram showed good predictive efficacy in the training and validation cohorts and may be useful for guiding clinical treatment of HCC patients. We also found that HCC cell-derived CXCL9 promoted N1 polarization of neutrophils in vitro and that AMG487, a specific CXCR3 inhibitor, significantly blocked this process. Moreover, multiple immunofluorescence (mIF) showed that patients with higher serum CXCL9 levels had greater infiltration of the N1 phenotype of tumor-associated neutrophils (TANs).
Our study highlights the critical role of CXCL9 as an effective biomarker of immunotherapy efficacy and in promoting the polarization of N1-type neutrophils; thus, targeting the CXCL9-CXCR3 axis could represent a novel pharmaceutical strategy to enhance immunotherapy for HCC.
抗程序性死亡蛋白1（PD1）抗体改变了肝细胞癌（HCC）的治疗格局，并展现出有前景的治疗效果。然而，大多数HCC患者仍对抗PD-1治疗无反应。
我们分析了接受抗PD-1治疗患者血液样本中CXCL9的表达，并评估其与临床病理特征及治疗结果的相关性。基于Cox回归分析结果，建立了预测HCC患者对抗PD-1治疗反应的列线图。分别利用qRT-PCR和多重免疫荧光检测分析体外及肿瘤样本中N1型中性粒细胞的比例。
该列线图在训练队列和验证队列中均显示出良好的预测效能，可能有助于指导HCC患者的临床治疗。我们还发现，HCC细胞来源的CXCL9在体外可促进中性粒细胞向N1极化，而特异性CXCR3抑制剂AMG487可显著阻断这一过程。此外，多重免疫荧光（mIF）显示，血清CXCL9水平较高的患者肿瘤相关中性粒细胞（TANs）的N1表型浸润程度更高。
我们的研究强调了CXCL9作为免疫治疗疗效的有效生物标志物以及促进N1型中性粒细胞极化的关键作用；因此，靶向CXCL9-CXCR3轴可能代表一种增强HCC免疫治疗的新型药物策略。
