Humoral contributions to checkpoint blockade therapy.

Area of Science:

• Immunology
• Oncology
• Proteomics

Background:

• Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment but shows variable patient responses.
• Understanding the heterogeneity in patient responses to ICB is crucial for improving efficacy.
• The role of autoantibodies in ICB response is an emerging area of research.

Purpose of the Study:

• To investigate the autoantibody landscape in patients undergoing ICB therapy.
• To identify specific autoantibodies associated with differential responses to ICB.
• To explore potential new therapeutic targets based on autoantibody profiles.

Main Methods:

• Utilized rapid extracellular antigen profiling to analyze circulating antibody profiles.
• Surveyed autoantibody profiles from 374 cancer patients and 131 healthy controls longitudinally.
• Conducted an autoantibody-wide association study to identify targeted autoantigens.

Main Results:

• Autoantibodies were more prevalent in ICB-treated cancer patients than in healthy controls.
• Specific autoantibodies targeting type-I interferon, IL-6, IL-17 pathways, or TL1A were associated with better ICB response, especially if neutralizing.
• Antibodies against bone morphogenesis proteins correlated with worse ICB response.

Conclusions:

• The autoantibody profile provides insights into patient response heterogeneity in ICB therapy.
• Targeting specific autoantigens or pathways may offer novel therapeutic strategies for enhancing ICB efficacy.
• Further investigation into the extracellular and secreted autoreactome is warranted for optimizing cancer immunotherapy.