Liu Zhi-Yong, Zhang Dan-Ying, Lin Xia-Hui, Sun Jia-Lei, Abuduwaili Weinire, Zhang Guang-Cong, Xu Ru-Chen, Wang Fu, Yu Xiang-Nan, Shi Xuan, Deng Bin, Dong Ling, Weng Shu-Qiang, Zhu Ji-Min, Shen Xi-Zhong, Liu Tao-Tao
Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China.
Shanghai Institute of Liver Disease, Shanghai, China.
Front Pharmacol. 2022 Aug 22;13:952482. doi: 10.3389/fphar.2022.952482. eCollection 2022.
Sorafenib resistance is often developed and impedes the benefits of clinical therapy in hepatocellular carcinoma (HCC) patients. However, the relationship between sorafenib resistance and tumor immune environment and adjuvant drugs for sorafenib-resistant HCC are not systemically identified. This study first analyzed the expression profiles of sorafenib-resistant HCC cells to explore immune cell infiltration levels and differentially expressed immune-related genes (DEIRGs). The prognostic value of DEIRGs was analyzed using Cox regression and Kaplan-Meier analysis based on The Cancer Genome Atlas. The primary immune cells infiltrated in sorafenib-resistant HCC mice were explored using flow cytometry (FCM). Finally, small-molecule drugs for sorafenib-resistant HCC treatment were screened and validated by experiments. The CIBERSORT algorithm and mice model showed that macrophages and neutrophils are highly infiltrated, while CD8 T cells are downregulated in sorafenib-resistant HCC. Totally, 34 DEIRGs were obtained from sorafenib-resistant and control groups, which were highly enriched in immune-associated biological processes and pathways. NR6A1, CXCL5, C3, and TGFB1 were further identified as prognostic markers for HCC patients. Finally, nalidixic acid was identified as a promising antagonist for sorafenib-resistant HCC treatment. Collectively, our study reveals the tumor immune microenvironment changes and explores a promising adjuvant drug to overcome sorafenib resistance in HCC.
索拉非尼耐药性经常出现，这阻碍了肝细胞癌（HCC）患者临床治疗的疗效。然而，索拉非尼耐药性与肿瘤免疫环境之间的关系以及索拉非尼耐药性HCC的辅助药物尚未得到系统鉴定。本研究首先分析了索拉非尼耐药性HCC细胞的表达谱，以探索免疫细胞浸润水平和差异表达的免疫相关基因（DEIRGs）。基于癌症基因组图谱，使用Cox回归和Kaplan-Meier分析来分析DEIRGs的预后价值。使用流式细胞术（FCM）探索了索拉非尼耐药性HCC小鼠中浸润的主要免疫细胞。最后，通过实验筛选并验证了用于治疗索拉非尼耐药性HCC的小分子药物。CIBERSORT算法和小鼠模型显示，在索拉非尼耐药性HCC中，巨噬细胞和中性粒细胞高度浸润，而CD8 T细胞下调。总共从索拉非尼耐药组和对照组中获得了34个DEIRGs，它们在免疫相关的生物学过程和途径中高度富集。NR6A1、CXCL5、C3和TGFB1被进一步鉴定为HCC患者的预后标志物。最后，萘啶酸被鉴定为治疗索拉非尼耐药性HCC的一种有前景的拮抗剂。总的来说，我们的研究揭示了肿瘤免疫微环境的变化，并探索了一种有前景的辅助药物来克服HCC中的索拉非尼耐药性。
