Low type-2 immune effectors modulate atopic diseases' protective role in pancreatic cancer risk

Studies reported that atopic individuals exhibit a 36% reduced risk of developing pancreatic ductal adenocarcinoma (PDAC); however, the underlying molecular mechanisms remain unclear. This study examines the specific role of type-2 immune response in the atopy-PDAC inverse association. To endotype atopic conditions using type-2 immune effectors (i.e., eosinophils and immunoglobulin-E[IgE]) and investigate their protective effect against PDAC risk, IgE levels were measured in 688 PDAC cases and 558 controls from the PanGenEU case-control study. 'IgE-sensitization' was defined as having >100 kU/L total IgE with lab-tested sensitization to ≥1 food- or aeroallergens. Atopic conditions were determined using the European Community Respiratory Health Survey questionnaire. The UK Biobank cohort's 544 PDAC cases and 92,038 nested controls were categorized based on a threshold of 0.15 × 10⁹ eosinophil cells/L plus self-reported atopy. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using multivariable logistic regression. Restricted cubic splines were applied to examine the nonlinear relationship between type-2 immune effectors and PDAC risk. PDAC risk was not linearly associated with type-2 immune effectors levels. Compared to low IgE-sensitized non-atopic individuals, the low IgE-sensitized atopic population had significantly reduced PDAC risk (OR = 0.56, 95% CI: 0.35-0.84). Similar trends were observed among atopic individuals with low eosinophil counts (OR = 0.67, 95% CI: 0.47-0.95). Atopic conditions were inversely associated with PDAC risk, particularly among those with low levels of type-2 immune effectors. This indicates the protective effect of atopy against PDAC risk is modulated by low type-2 immune response.