HFE polymorphism negatively impacts pancreatic cancer progression and anti-tumor immune response

Homeostatic Iron regulator, known as HFE, is the main altered gene in the Hereditary Hemochromatosis (HH) disease. Of the two main HFE polymorphisms, H63D rarely causes overt HH symptoms, but has been described as a risk factor for the development of cancer. Little is known about H63D’s impact on Pancreatic Ductal Adenocarcinoma (PDAC), a devastating disease that still represents an unmet medical need. The few curing progresses achieved through the years compared to other types of cancer still underline the necessity of finding strategies to better stratify and manage PDAC patients. Accordingly, this thesis aimed at characterizing the immune response in spontaneous PDAC mouse models, namely KC and KPC mice, in the absence or presence of H67D mutation (KC/HfeH67D/H67D and KPC/HfeH67D/H67D), the murine orthologue of H63D. Histological analyses of tumors arose in mutated PDAC-bearing mice evidenced an increased tumor aggressiveness, with a higher propensity to metastasize and contact ganglia into the organ. Functionally, H67D-bearing mice were able to mount an antigen-specific immune response, but in vitro experiments evidenced a tendency towards a suppressive type-II response with, however, a massive production of antibodies. Ex vivo analyses confirmed H67D tumors being more aggressive and more infiltrated by suppressive cells. KC/HfeH67D/H67D mice at 3 months were comparable in lesion extension and number of infiltrating cells to KC mice at 6 months, even though such immune cells strongly differed from a functional point of view. Therefore, the H67D polymorphism significantly impacts PDAC progression and strongly affects immune cell activation, representing a promising prognostic biomarker that deserves further investigations to better manage and treat PDAC patients.