Introduction/Rationale: The homeostatic iron regulator (HFE) gene is altered in hereditary hemochromatosis. The histidine-to-aspartic acid substitution at position 63 (H63D) rarely causes overt disease but is associated with increased cancer risk. Its role in pancreatic ductal adenocarcinoma remains unclear, despite its high prevalence among resectable patients with reduced post-surgical survival.
Methods: To assess the impact of H63D on anti-tumor immunity, Kras^G12D;Pdx1-Cre (KC) mice were crossed with mice carrying the H67D mutation, the murine ortholog of H63D. Tumor growth, metastasis, immune infiltrates, and antigen-specific immune responses were evaluated in vivo and ex vivo.
Results: H67D-bearing mice showed accelerated tumor growth and early metastatic dissemination to the lung and liver. At comparable tumor burden, KC/H67D tumors exhibited reduced lymphoid infiltrates and enrichment of myeloid populations, consistent with a type II regulatory immune bias and reduced survival. Although KC/H67D mice mounted antigen-specific immune responses and produced elevated antigen-specific antibodies, tumor growth was enhanced in both subcutaneous and orthotopic models. Ex vivo analyses revealed impaired interferon-γ (IFN-γ) production with increased interleukin-4 (IL-4) secretion. Accordingly, KC/H67D tumors displayed eosinophilia and increased suppressive immune cell accumulation.
Conclusion: These findings identify the H63D/H67D polymorphism as a driver of immune dysregulation that accelerates pancreatic cancer progression and supports its potential as a clinically relevant immunological biomarker.
