PDF(Pubmed)
Abstract：
Bevacizumab is a recombinant humanized monoclonal immunoglobulin (Ig) G1 antibody of VEGF, and inhibits angiogenesis and tumor growth in hepatocellular carcinoma (HCC). Ferroptosis, a new form of regulated cell death function independently of the apoptotic machinery, has been accepted as an attractive target for pharmacological intervention; the ferroptosis pathway can enhance cell immune activity of anti-PD1 immunotherapy in HCC. In this study we investigated whether and how bevacizumab regulated ferroptosis and immune activity in liver cancer. Firstly, we performed RNA-sequencing in bevacizumab-treated human liver cancer cell line HepG2 cells, and found that bevacizumab significantly altered the expression of a number of genes including VEGF, PI3K, HAT1, SLC7A11 and IL-9 in liver cancer, bevacizumab upregulated 37 ferroptosis-related drivers, and downregulated 17 ferroptosis-related suppressors in particular. We demonstrated that bevacizumab triggered ferroptosis in liver cancer cells by driving VEGF/PI3K/HAT1/SLC7A11 axis. Clinical data confirmed that the expression levels of VEGF were positively associated with those of PI3K, HAT1 and SLC7A11 in HCC tissues. Meanwhile, we found that bevacizumab enhanced immune cell activity in tumor immune-microenvironment. We identified that HAT1 up-regulated miR-143 targeting IL-9 mRNA 3\'UTR in liver cancer cells; bevacizumab treatment resulted in the increase of IL-9 levels and its secretion via VEGF/PI3K/HAT1/miR-143/IL-9 axis, which led to the inhibition of tumor growth in vivo through increasing the release of IL-2 and Granzyme B from activated CD8+ T cells. We conclude that in addition to inhibiting angiogenesis, bevacizumab induces ferroptosis and enhances CD8+ T cell immune activity in liver cancer. This study provides new insight into the mechanisms by which bevacizumab synergistically modulates ferroptosis and CD8+ T cell immune activity in liver cancer.
摘要：
贝伐单抗是VEGF的重组人源化单克隆免疫球蛋白(Ig)G1抗体,并抑制肝细胞癌（HCC）的血管生成和肿瘤生长。Ferroptosis,一种新形式的调节细胞死亡功能，独立于凋亡机制，已被认为是药物干预的有吸引力的靶标；铁凋亡途径可以增强肝癌中抗PD1免疫治疗的细胞免疫活性。在这项研究中，我们调查了贝伐单抗是否以及如何调节肝癌中的铁细胞凋亡和免疫活性。首先,我们在贝伐单抗治疗的人肝癌细胞系HepG2细胞中进行了RNA测序，发现贝伐单抗显著改变了包括VEGF在内的许多基因的表达，PI3K,HAT1，SLC7A11和IL-9在肝癌中的作用，贝伐单抗上调了37个铁凋亡相关驱动因素，特别是下调了17种与铁凋亡相关的抑制因子。我们证明，贝伐单抗通过驱动VEGF/PI3K/HAT1/SLC7A11轴在肝癌细胞中引发铁凋亡。临床资料证实VEGF的表达水平与PI3K的表达水平呈正相关,HAT1和SLC7A11在肝癌组织中的表达。同时,我们发现贝伐单抗可增强肿瘤免疫微环境中的免疫细胞活性.我们发现HAT1在肝癌细胞中上调靶向IL-9mRNA3'UTR的miR-143;贝伐单抗治疗导致IL-9水平及其通过VEGF/PI3K/HAT1/miR-143/IL-9轴的分泌增加，通过增加IL-2和颗粒酶B从活化的CD8T细胞中的释放，从而抑制了体内肿瘤的生长。我们得出结论，除了抑制血管生成，贝伐单抗在肝癌中诱导铁凋亡并增强CD8+T细胞免疫活性。这项研究为贝伐单抗协同调节肝癌中铁凋亡和CD8+T细胞免疫活性的机制提供了新的见解。
