Causal Links Between Antibody-Mediated Immune Responses and Pancreatic Cancer Risk

Pancreatic cancer (PC) presents unique challenges to traditional immunotherapy due to its immunosuppressive microenvironment and low mutation burden. Research into antibody-mediated immune responses, which has been extensively applied in various cancer types, is also applicable to the study of pancreatic cancer.

Using public Genome-wide association study (GWAS) data and genetic instruments, we conducted a two-sample Mendelian randomization (MR) analysis to explore causal relationships between 46 antibody-mediated immune responses and PC. We employed five MR methods. Cochran's Q statistic and corresponding p-values from the MR Egger and Inverse Variance Weighted methods assessed instrument heterogeneity. Egger intercept and MR pleiotropy residual sum and outlier (MR-PRESSO) methods detected potential horizontal pleiotropy, ensuring the robustness of our findings.

Our study identified causal links between five antibody-mediated immune responses and pancreatic cancer risk. Chlamydia trachomatis momp A antibody levels were inversely correlated, while Anti-helicobacter pylori IgG seropositivity, Polyomavirus 2 JC VP1 antibody levels, and Merkel cell polyomavirus VP1 antibody levels showed positive correlations. Notably, Anti- Merkel cell polyomavirus IgG seropositivity exhibited strong positive associations across Inverse variance weighting (IVW), weighted median, and MR-Egger analyses (p < 0.05).

These results suggest that specific Antibody-Mediated Immune Responses may modulate pancreatic carcinogenesis through immune activation or chronic inflammation. The protective association for Chlamydia trachomatis momp A contrasts with the risk-enhancing effects observed for anti-helicobacter pylori IgG and polyomaviruses, highlighting heterogeneous immunobiological pathways that warrant mechanistic investigation.

Our study demonstrated a randomized causal effect between antibody-mediated immune responses and pancreatic cancer, offering a new perspective for clinical diagnosis and treatment of the disease.