Innate and adaptive immune features associated with immune-related adverse events.

Area of Science:

• Immunology
• Oncology
• Translational Medicine

Background:

• Immune checkpoint inhibitors (ICIs) are effective cancer treatments but can cause severe immune-related adverse events (irAEs).
• Understanding the biological mechanisms underlying irAEs is crucial for patient safety and treatment optimization.

Purpose of the Study:

• To characterize the peripheral immune landscape associated with irAE development in patients receiving ICI therapy.
• To identify potential biomarkers for predicting irAEs.

Main Methods:

• Multidimensional analysis including single-cell RNA sequencing, mass cytometry, cytokine assays, and antinuclear antibody (ANA) profiling.
• Characterization of peripheral immune cells and gene expression in 162 patients undergoing ICI therapy, comparing those with and without irAEs.

Main Results:

• Patients developing irAEs showed a baseline proinflammatory, autoimmune-like state with increased CD57+ T/NK cells, plasmablasts, activated lymphocytes, and elevated ANA levels.
• Distinct baseline proinflammatory gene signatures (e.g., IL1B, CXCL8, CXCR3, TNF, IFNG) and enriched TNF signaling were observed in irAE patients.
• Patients without irAEs had increased baseline immunosuppressive markers and distinct myeloid reprogramming.

Conclusions:

• A pre-existing activated, autoimmune-like proinflammatory state drives irAE development via plasmablast/ANA, IFN-gamma/CXCL10/CXCR3, and TNF signaling axes.
• These findings suggest potential peripheral immune biomarkers for irAE prediction.
• The study provides biological insights into irAE mechanisms, potentially guiding mitigation strategies.