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Mechanisms of Resistance to Immunotherapy in Hepatocellular Carcinoma
Giulia Francesca Manfredi1,2, Ciro Celsa1,3,4, Chloe John1
1Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK.
Abstract:
Systemic treatment for advanced hepatocellular carcinoma (HCC) has been revolutionized over the last few years following the approval of immune checkpoint inhibitors (ICI). Despite the promising survival extension seen with ICI combination regimens, responses are not universally seen and the optimal partner for programmed cell death 1 pathway inhibitors remains to be identified. Even fewer encouraging results have been demonstrated with ICI used for monotherapy. Several mechanisms of resistance have been described so far, involving characteristics of cancer cells (intrinsic mechanisms) and of the surrounding tumor microenvironment (extrinsic mechanisms). Factors related to therapy may also contribute to the development of resistance. Increasing research efforts are being dedicated to the discovery of novel approaches and targets to overcome resistance, some of which may be introduced into clinic in the future. Herein we describe a selection of resistance mechanisms that have been involved in impairing response to ICI and propose potential therapeutic approaches to overcome resistance.
Insights
Immune checkpoint inhibitors (ICI) have transformed advanced liver cancer treatment. However, resistance limits their effectiveness, necessitating research into overcoming these challenges for better patient outcomes.
Area of Science:
- Hepatocellular carcinoma (HCC) research
- Immunotherapy
- Cancer resistance mechanisms
Background:
- Systemic treatment for advanced hepatocellular carcinoma (HCC) has been significantly improved by immune checkpoint inhibitors (ICI).
- While ICI combinations offer survival benefits, not all patients respond, and the ideal ICI partner is unknown.
- Monotherapy with ICI has shown limited efficacy, highlighting the need to understand resistance.
Purpose of the Study:
- To review known mechanisms of resistance to immune checkpoint inhibitors in advanced HCC.
- To explore potential therapeutic strategies to overcome ICI resistance.
- To identify future directions for improving immunotherapy response in HCC.
Main Methods:
- Literature review of resistance mechanisms in HCC treated with ICI.
- Analysis of intrinsic (cancer cell) and extrinsic (tumor microenvironment) resistance factors.
- Discussion of therapeutic approaches to overcome resistance.
Main Results:
- Multiple intrinsic and extrinsic mechanisms contribute to ICI resistance in HCC.
- Therapeutic factors can also influence the development of resistance.
- Novel approaches are under investigation to improve ICI efficacy.
Conclusions:
- Understanding resistance mechanisms is crucial for advancing HCC immunotherapy.
- Targeting resistance pathways offers potential for improved patient survival.
- Future research should focus on combination therapies and novel targets to overcome ICI resistance.
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