Complement contributes to ICI-triggered sialadenitis and predicts ICI efficacy

While highly efficacious for numerous cancers, immune checkpoint inhibitors (ICIs) can cause unpredictable and potential immune-related adverse events (irAEs). In this study, we aimed to unveil the underlying mechanisms for sialadenitis irAEs under cancer context and assess the response-associated biomarkers for ICI therapy. We found that cholangiocarcinoma patients receiving anti-PD-1 agent showed dry symptoms, and a declined level of serum complement and immune compound were also observed when compared to those without anti-PD-1 treatment. We further demonstrated that the elevated complement activation caused initial salivary gland damage through complement-dependent cytotoxicity after anti-PD-1 administration, which subsequently led to glandular lymphocyte infiltration and dysfunction. We then determined that complement pathway blockade effectively reverse sialadenitis and dysfunction, while anti-PD-1 administration in vivo. Moreover, we determined that sialadenitis irAEs was associated with improved survival rate and ICI response in cholangiocarcinoma. Our findings provided a distinct mechanism showing the occurrence of sialadenitis during ICI treatment, which may explore available biomarkers for ICI efficacy and provide basis for improving ICI application in malignancies.