Targeting AXL induces tumor-intrinsic immunogenic response in tyrosine kinase inhibitor-resistant liver cancer

  • Cell Death Dis. 2024 Feb 3;15(2):110. doi: 10.1038/s41419-024-06493-0.
Yunong Xie  1  2 ,  Haofeng Wu  1 ,  Yimiao He  1 ,  Linglin Liu  1 ,  Ianto Bosheng Huang  2 ,  Lei Zhou  2  3 ,  Cheuk-Yin Lin  2 ,  Rainbow Wing-Hei Leung  4 ,  Jia-Jian Loh  2 ,  Terence Kin-Wah Lee  4 ,  Jin Ding  5 ,  Kwan Man  6  7 ,  Stephanie Ma  8  9  10 ,  Man Tong  11  12
Affiliations
  • 1. School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
  • 2. School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • 3. Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
  • 4. Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China.
  • 5. Clinical Cancer Institute, Center for Translational Medicine, Naval Medical University, Shanghai, China.
  • 6. Department of Surgery, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • 7. State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China.
  • 8. School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China. [email protected].
  • 9. State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China. [email protected].
  • 10. Hong Kong University-Shenzhen Hospital, Shenzhen, China. [email protected].
  • 11. School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China. [email protected].
  • 12. School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China. [email protected].
PMID: 38310091 DOI: 10.1038/s41419-024-06493-0
Abstract

Hepatocellular carcinoma (HCC) is an aggressive malignancy without effective therapeutic approaches. Here, we evaluate the tumor-intrinsic mechanisms that attenuate the efficacy of immune checkpoint inhibitor (ICI) that is observed in patients with advanced HCC who progress on first-line tyrosine kinase inhibitor (TKI) therapy. Upregulation of Axl observed in sorafenib- and lenvatinib-resistant HCCs is correlated with poor response towards TKI and ICI treatments. Axl upregulation protects sorafenib-resistant HCC cells from oxidative stress, mitochondrial damage, and accompanying immunogenic cell death through suppressed tumor necrosis factor-α (TNF-α) and STING-type I interferon pathways. Pharmacological inhibition of Axl abrogates the protective effect and re-sensitizes TKI-resistant HCC tumors to anti-PD-1 treatment. We suggest that targeting Axl in combination with anti-PD-1 may provide an alternative treatment scheme for HCC patients who progress on TKI treatment.

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