Iron-overload affects anti-tumor immune response in pancreatic cancer.

Abstract

Abstract HFE is the most frequently mutated gene in hereditary hemochromatosis, a disease in which iron accumulates in organs leading to toxicities. Worldwide, two main polymorphisms in HFE protein have been observed, namely C282Y and H63D. Even if associated to milder iron accumulations, H63D polymorphism increases the risk of cancer development and aggressiveness. As observed in pancreatic cancer patients, a great percentage of those that underwent to surgery also present H63D polymorphism but displayed a worse survival. To better characterize how the iron accumulation affects anti-tumor response in the context of the pancreatic ductal adenocarcinoma (PDA), we crossed genetically engineered mice (GEM) that spontaneously develop PDA with mice engineered to express H67D mutation (HfeH67D), the orthologue of H63D in human. Histological analysis of GEM showed that H67D polymorphism accelerated PDA progression, increased the number of metastases, and altered the composition of infiltrating immune cells. Accordingly, these mouse models also displayed a reduced overall survival compared to controls. By exploiting OVA as a well-known antigen, we injected OVA-expressing PDA cells subcutaneously in mice carrying or not the H67D mutation to assess their ability to mount a normal memory response. OVA-expressing PDA cells grew faster in the presence of H67D polymorphism, but immunized mice displayed a reduction in tumor volume similar to the WT counterpart. HfeH67Dmice displayed an increased production of anti-OVA IgG antibodies, especially IgE, but a decreased in OVA-specific IFNγ-secreting T cells. Overall, H67D polymorphism impacts the activation of anti-tumoral immune response, which consequently worsens PDA progression. Supported by grants from AIRC (ID22234; ID26341)