Intestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration.

Area of Science:

• Oncology
• Immunology
• Gastroenterology

Background:

• Immune checkpoint blockade (ICB) offers significant cancer treatment benefits but is limited by immune-related adverse events (irAEs).
• Mechanisms underlying irAEs, particularly gastrointestinal toxicity, remain poorly understood, hindering mitigation strategies.

Purpose of the Study:

• To investigate the impact of disrupted gut homeostatic immunity on anti-CTLA-4 (αCTLA-4)-mediated toxicity.
• To identify immune signatures associated with αCTLA-4-induced irAEs and explore therapeutic interventions.

Main Methods:

• Utilized mouse models with genetic predisposition to intestinal inflammation, gastrointestinal infection, dysbiotic microbiome transplantation, and dextran sodium sulfate administration.
• Analyzed colonic tissue and systemic markers, including neutrophil accumulation and interleukin-6 (IL-6) levels.
• Validated findings in human patient biopsies from cases of ICB colitis.

Main Results:

• αCTLA-4 treatment exacerbated inflammation and colonic tissue damage in mice with compromised gut immunity.
• An immune signature of αCTLA-4 irAEs involved colonic neutrophil infiltration and systemic IL-6 release.
• Combined IL-6 blockade and antibiotic treatment reduced intestinal damage and enhanced αCTLA-4 efficacy in susceptible mice.

Conclusions:

• Disruption of gut homeostasis sensitizes to αCTLA-4-induced intestinal irAEs.
• IL-6 blockade and antibiotics represent a potential strategy to mitigate irAEs and improve ICB therapy.
• Findings provide preclinical models and mechanistic insights for managing ICB-related toxicity.