Complement contributes to ICI-triggered sialadenitis and predicts ICI efficacy

Area of Science:

• Oncology
• Immunology
• Pathology

Background:

• Immune checkpoint inhibitors (ICIs) are effective cancer treatments but can cause immune-related adverse events (irAEs).
• Sialadenitis, an irAE affecting salivary glands, requires mechanistic understanding for improved ICI therapy.
• Identifying biomarkers for ICI response is crucial for optimizing cancer treatment.

Purpose of the Study:

• To elucidate the mechanism of sialadenitis irAEs in cholangiocarcinoma patients treated with anti-PD-1 agents.
• To identify biomarkers associated with ICI therapy response.
• To evaluate the therapeutic potential of complement pathway blockade.

Main Methods:

• Analysis of cholangiocarcinoma patients receiving anti-PD-1 therapy.
• Measurement of serum complement and immune compounds.
• In vivo studies assessing complement activation, salivary gland damage, and therapeutic interventions.

Main Results:

• Anti-PD-1 treatment in cholangiocarcinoma patients correlated with dry mouth symptoms and decreased serum complement/immune compounds.
• Elevated complement activation was identified as the cause of salivary gland damage via complement-dependent cytotoxicity.
• Complement pathway blockade reversed sialadenitis and dysfunction in vivo.
• Sialadenitis irAEs were associated with improved survival and ICI response.

Conclusions:

• Complement activation is a key mechanism underlying anti-PD-1-induced sialadenitis.
• Complement pathway blockade shows therapeutic promise for managing this irAE.
• Sialadenitis may serve as a predictive biomarker for ICI efficacy in cholangiocarcinoma.