Primary and acquired resistance to PD-1/PD-L1 blockade in cancer treatment

Area of Science:

• Immunology
• Oncology
• Cancer Research

Background:

• Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade offers significant clinical benefits in various cancers.
• Primary and acquired resistance limit the effectiveness of PD-1/PD-L1 blockade therapy.
• Mechanisms underlying resistance to PD-1/PD-L1 blockade are not fully understood.

Purpose of the Study:

• To review current understanding of resistance mechanisms to PD-1/PD-L1 blockade.
• To elucidate factors contributing to primary and acquired resistance.
• To briefly discuss potential therapeutic strategies for overcoming resistance.

Main Methods:

• Literature review of current research on PD-1/PD-L1 blockade resistance.
• Detailed documentation of identified resistance mechanisms.
• Synthesis of information on immunoregulatory factors, transcriptomic signatures, and cancer-cell-autonomous cues.

Main Results:

• Primary resistance is linked to immunoregulatory factors, innate anti-PD-1 resistance (IPRES) signatures, and cancer-cell-autonomous cues.
• Acquired resistance involves neoantigen evolution, JAK/β-2-microglobulin mutations, and epigenetic stability of exhausted T cells.
• Multiple factors contribute to both initial non-response and eventual treatment failure.

Conclusions:

• Understanding the multifaceted mechanisms of PD-1/PD-L1 blockade resistance is essential.
• Targeting identified resistance pathways may improve immunotherapy efficacy.
• Further research into therapeutic strategies is needed to sensitize resistant tumors.