Acquired Resistance to Immune Checkpoint Blockades: The Underlying Mechanisms and Potential Strategies

Area of Science:

• Oncology
• Immunology
• Cancer Research

Background:

• Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, offering durable responses in many patients.
• Acquired resistance to ICB therapy is a significant clinical challenge, limiting its long-term efficacy.
• Current knowledge on acquired resistance mechanisms is fragmented and requires comprehensive summarization.

Purpose of the Study:

• To clarify the principal elements and mechanisms of acquired resistance to immune checkpoint blockade therapy.
• To provide a consolidated overview of factors contributing to treatment failure in ICB therapy.
• To inform future research directions for overcoming ICB resistance.

Main Methods:

• This review synthesizes existing literature on acquired resistance to immune checkpoint blockade therapy.
• It defines acquired resistance based on expert consensus, notably from The Society for Immunotherapy of Cancer.
• Mechanisms are categorized into tumor-intrinsic and tumor-extrinsic factors.

Main Results:

• Oligo-progression is identified as the primary pattern of acquired resistance.
• Acquired resistance can arise from pre-existing resistant cancer clones or gradual adaptation of sensitive cells.
• Tumor-intrinsic mechanisms include neoantigen depletion, antigen presentation defects, interferon signaling aberrations, immune suppression, and tumor cell plasticity.
• Tumor-extrinsic mechanisms involve the upregulation of other immune checkpoints.

Conclusions:

• Understanding the diverse mechanisms of acquired resistance is crucial for improving ICB therapy outcomes.
• Current strategies to overcome resistance are applied broadly and require further research.
• Targeted interventions based on specific resistance mechanisms are needed to enhance patient responses to ICB therapy.