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An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
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Notch Signaling and PD-1/PD-L1 Interaction in Hepatocellular Carcinoma: Potentialities of Combined Therapies

Annapaola Montagner1,2, Andrea Arleo1, Fabrizia Suzzi1

  • 1Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy.

Biomolecules
|January 8, 2025
PubMed

Insights

Immunotherapy improves survival in hepatocellular carcinoma (HCC), but resistance necessitates new treatments. Combining Notch signaling inhibition with immune checkpoint inhibitors (ICIs) may overcome resistance and improve HCC outcomes.

Area of Science:

  • Hepatocellular carcinoma (HCC) research
  • Cancer immunotherapy
  • Molecular signaling pathways

Background:

  • Immunotherapy, specifically immune checkpoint inhibitors (ICIs), offers improved survival for hepatocellular carcinoma (HCC) patients over tyrosine kinase inhibitors (TKIs).
  • A significant subset of HCC (approximately 30%) displays intrinsic resistance to ICIs, highlighting the urgent need for novel therapeutic strategies.
  • Dysregulation of the Notch signaling pathway in HCC can negatively impact immune cell function, thereby diminishing the effectiveness of current cancer immunotherapies.

Purpose of the Study:

  • To explore the role of Notch signaling in regulating immune responses within the tumor microenvironment of HCC.
  • To establish the therapeutic rationale for combining Notch signaling inhibition with ICIs to enhance treatment efficacy in HCC.
  • To propose the use of exosomes for non-invasive assessment of Notch signaling activation in HCC, facilitating patient stratification for combination therapies.

Main Methods:

  • Literature review on Notch signaling pathways and their interaction with immune cells in HCC.
  • Analysis of the mechanisms by which Notch signaling influences immune evasion in hepatocellular carcinoma.
  • Exploration of exosome-based biomarkers for Notch signaling activity in hepatic cancer.

Main Results:

  • Notch signaling pathway dysregulation is implicated in immune resistance within the HCC tumor microenvironment.
  • Inhibition of Notch signaling presents a viable strategy to potentially sensitize HCC tumors to ICI therapy.
  • Exosomes can serve as non-invasive indicators of Notch signaling activation, aiding in the selection of patients for combination treatments.

Conclusions:

  • Combining Notch signaling inhibition with ICIs is a promising therapeutic approach to overcome intrinsic ICI resistance in HCC.
  • Non-invasive assessment of Notch signaling via exosomes can enable personalized treatment strategies for HCC patients.
  • Further research into Notch signaling modulation and exosome-based diagnostics is warranted to optimize HCC immunotherapy.
Keywords:
NotchPD-1PD-L1combination therapyhepatocellular carcinoma (HCC)immunotherapy

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