Immunotherapy-induced sialadenitis: sjögren's syndrome or a new sialadenitis.

[OBJECTIVE] Although immune checkpoint inhibitors (ICIs) have improved survival in head and neck squamous cell carcinoma (HNSCC), associated adverse events, such as sialadenitis, remain poorly characterized. This study aimed to define the clinicopathological features, establish the causal pathogenic mechanism, and validate a therapeutic target for ICI-associated sialadenitis.

[METHODS] This study integrated three complementary approaches. First, a prospective cohort of 25 HNSCC patients underwent functional assessment of salivary and lacrimal glands before and after ICI therapy. Second, salivary gland tissues from separate cohorts of ICI-treated (n=30) and untreated control (n=30) patients were subjected to comprehensive analysis, including histology, multi-platform immunophenotyping (immunohistochemistry, multiplex immunofluorescence, flow cytometry), and cytokine quantification at both transcript and protein levels. Finally, a preclinical mouse model was established to confirm causality and validate the therapeutic efficacy of IL-17A blockade.

[RESULTS] Following ICI treatment, patients showed significantly reduced salivary and lacrimal secretion ( 0.05). Histopathological analysis revealed extensive lymphocytic infiltration, marked periductal fibrosis, and substantial loss of acinar structures. The immune infiltrate was dominated by CD4 T cells, particularly the Th17 subset, with corresponding upregulation of IL-17A both at transcriptional and protein levels. Crucially, we established a mouse model of anti-PD-1-induced sialadenitis and demonstrated that therapeutic blockade of IL-17A restores salivary function.

[CONCLUSION] This study establishes ICI-associated sialadenitis as a distinct pathological entity characterized by CD4T cell-driven inflammation mediated through the Th17/IL-17 axis, which differs from Sjögren syndrome, predominantly involving B cells and from IgG4 related sialadenitis. By demonstrating therapeutic efficacy in a preclinical model, our findings provide the first preclinical validation of the IL-17 axis as an actionable therapeutic target for this condition.