Th1/Th2 immune polarization and cancer of unknown primary (CUP) risk in autoimmune disease: A global healthcare cohort study.

Abstract

e14550 Background: Cancer of unknown primary (CUP) represents 2–5% of global malignancies and remains among the top 10 cancers despite advances in imaging, molecular diagnostics, and immunotherapy. Prior studies show increased CUP risk in autoimmune diseases, but the influence of inflammatory patterns is unclear. Emerging data suggest Type 2 inflammation promotes tumorigenesis through IL-4/IL-13–driven proliferation, Bcl-2/Bcl-xL–mediated apoptosis resistance, and M2/MDSC-mediated immunosuppression, whereas Type 1 inflammation enhances IFN-γ responses, M1 activation, and direct tumor cytotoxicity. We hypothesized that Th1 versus Th2 inflammatory signatures differentially affect CUP development. Methods: Using the TriNetX global research network (2010-2024), we identified adults (≥18 years) with a total of 36 autoimmune diseases stratified by predominant inflammatory pattern: Type 1 (rheumatoid arthritis, multiple sclerosis, Crohn's disease), Type 2 or mixed (Sjögren syndrome, SLE, dermatomyositis, ulcerative colitis), and vasculitis. Propensity score matching (1:1) generated matched controls without autoimmune disease. Cox proportional hazards models estimated hazard ratios (HR) and odds ratio (OD) adjusting for age, sex, race, smoking, and HIV/AIDS. Diagnosis of ADHD was included as internal control. Results: After matching, 4,334,934 patients were included (median follow-up 3.3 years). CUP occurred in 2,406 patients with autoimmune disease versus 1,101 controls (HR 2.19, 95% CI 2.04–2.35, p < 0.0001). Sixteen autoimmune diseases were associated with increased CUP risk. Stratification showed higher risk in Th2-dominant or mixed diseases (HR 2.50, 95% CI 2.43–2.57) compared with Th1-dominant diseases (HR 2.04, 95% CI 1.94–2.15), supporting a role for chronic Type 2 inflammation in creating an immunosuppressive tumor microenvironment. Addison’s disease showed the highest individual risk (HR 3.68, 95% CI 1.98–6.76), possibly reflecting chronic steroid exposure. Patients with multiple autoimmune diseases had markedly higher risk (HR 2.89, 95% CI 2.53–3.30) than those with a single disease (HR 1.88, 95% CI 1.74–2.03), suggesting cumulative immune dysregulation. Biomarker and treatment comparisons showed no significant differences in MSI-H or HER2 positivity. Likewise, there is no difference for use of platinum chemotherapy (OR 1.12, 95% CI 0.65–1.92) or HER2-targeted therapy (OR 0.82, 95% CI 0.50–1.36). CUP patients with certain autoimmune diseases were more likely to receive immune checkpoint inhibitors (OR 1.25, 95% CI 1.06–1.46). Conclusions: This large real-world study shows that Type 2 inflammatory autoimmune diseases confer higher CUP risk than Type 1 diseases, and that multiple autoimmune diseases further amplify risk, highlighting immune dysregulation as a key pathogenic driver.