2. Academic Validation
  3. Targeting AXL induces tumor-intrinsic immunogenic response in tyrosine kinase inhibitor-resistant liver cancer

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

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. stefma@hku.hk.
  • 9 State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China. stefma@hku.hk.
  • 10 Hong Kong University-Shenzhen Hospital, Shenzhen, China. stefma@hku.hk.
  • 11 School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China. carolmantong@cuhk.edu.hk.
  • 12 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China. carolmantong@cuhk.edu.hk.
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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