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Bevacizumab induces ferroptosis and enhances CD8+ T cell immune activity in liver cancer via modulating HAT1 and increasing IL-9

Acta Pharmacologica Sinica (2024)Cite this article

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.

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Fig. 1: Bevacizumab-induced profiling confers ferroptosis in liver cancer.
Fig. 2: Bevacizumab is capable of inducing ferroptosis in liver cancer.
Fig. 3: Bevacizumab triggers ferroptosis by driving VEGF/PI3K/HAT1/SLC7A11 axis in liver cancer.
Fig. 4: Bevacizumab increases the levels of IL-9 and its secretion by VEGF/PI3K/HAT1/miR-143/IL-9 axis in liver cancer.
Fig. 5: Bevacizumab accelerates ferroptosis and stimulates immune cell activity in vivo.
Fig. 6: Bevacizumab triggers ferroptosis and CD8+ T cell immune activity in a model.

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Data availability

The RNA-Seq data are available at the Sequence Read Archive (https://www.ncbi.nlm.nih.gov/sra/), accession number: SUB14146476.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82372818 to XDZ; 82103066 to GY; 82302887 to HFY; 82303210 to YFW), The China Postdoctoral Science Foundation (2022M712389 to HFY; 2023M732624 to YFW; 2023M742621 to LNZ).

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Authors and Affiliations

  1. National Key Laboratory of Draggability Evaluation and Systematic Translational Medicine, Tianjin’s Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Department of Gastrointestinal Cancer Biology, Tianjin Cancer Institute, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China

    Chun-yu Hou, Pan Lv, Hong-feng Yuan, Li-na Zhao, Yu-fei Wang, Hui-hui Zhang, Guang Yang & Xiao-dong Zhang

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  1. Chun-yu Hou
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Contributions

XDZ, GY, and CYH concepted and designed the project; HFY Developed the methodology; CYH acquired the data Acquisition of data (provided animals, provided facilities, etc.); CYH, LNZ, YFW, HHZ, and PL analyzed and interpreted the data (e.g., statistical analysis, biostatistics, computational analysis); CYH and XDZ written, reviewed, and/or revised of the manuscript.

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Correspondence to Guang Yang or Xiao-dong Zhang.

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Hou, Cy., Lv, P., Yuan, Hf. et al. Bevacizumab induces ferroptosis and enhances CD8+ T cell immune activity in liver cancer via modulating HAT1 and increasing IL-9. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01299-4

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