Association of immune checkpoint inhibitor-induced bullous pemphigoid with underlying cancer type: A lack of association with cancer tissue COL17A1 mutations and dysregulation

Abstract

Bullous pemphigoid (BP) is an autoimmune blistering disease caused by autoantibodies to collagen type 17 (COL17A1) and is a recognized immune-related adverse event in patients receiving immune checkpoint inhibitors (ICIs). We investigated whether cancer type influences the risk of developing ICI-induced BP and whether COL17A1 mutations or dysregulation in tumor tissue contributes to disease-specific variation. Using TriNetX, systematic review, and bioinformatics datasets, we comprehensively assessed the associations of ICI-induced BP with different malignancy types as well as COL17A1 gene expression, mutation frequency, and immune correlations across cancers. Lung cancer was the most common underlying malignancy in ICI-induced BP, but nonmelanoma skin cancer and renal cell carcinoma had the highest relative risk, whereas lung cancer had the lowest. ICI-induced BP was associated with improved survival across several cancers. Urothelial cancer showed the shortest time to onset, whereas renal cell carcinoma showed the longest. Cutaneous squamous cell carcinoma and melanoma exhibited the highest COL17A1 mutation burden, whereas renal cell carcinoma had a low burden. COL17A1 was overexpressed in several cancers but underexpressed in melanoma, without strong correlation to tumor-infiltrating immune cells. Although the incidence of ICI-induced BP significantly differed on the basis of cancer type, COL17A1 mutations or dysregulation do not appear to drive this phenomenon, suggesting alternative immune mechanisms.