Cellular origin influences the immune microenvironment in a pancreatic cancer mouse model with loss of Pten and activation of KRAS

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with an overall 5-year survival rate of merely 10%. Mouse studies in the past decade have made progress towards a better understanding of how PDAC cellular origin affects tumorigenesis. However, there is little study done on the immune microenvironment differences between acinar and ductal cell-derived precursor lesions and PDAC. Following our previous study that showed loss of Pten with oncogenic KrasG12D mutations in the ductal cells (KPtenΔDuct/+) resulted the formation of intraductal papillary mucinous neoplasias (IPMN) as the precursor lesion in mice, we further found similar mutations in the acinar cells (KPtenΔAcinar/+) formed pancreatic intraepithelial neoplasia (PanIN) instead. I subsequently used the KPtenΔDuct/+and KPtenΔAcinar/+ models to elucidate the effect of cellular origin on the immune microenvironment by performing immunohistochemistry. I focused on immune cell infiltration densities in precursor lesions and PDAC derived from KPtenΔDuct/+ and KPtenΔAcinar/+ mice and found that immune cell population and its changes throughout tumorigenesis are different starting at a precursor lesion stage between these two models. Additionally, macrophages polarized by conditioned media derived from KPtenΔDuct PDAC cells were polarized in less magnitude compared with macrophages polarized by KPtenΔAcinar PDAC cells. This difference in polarization was at least partially due to the lower expression of GM-CSF in KPtenΔDuct PDAC cells. Our study is the first to directly compare immune cell population between acinar- and ductal-derived PDAC with the same genetic background. Our study suggests cellular origin could influence PDAC immune heterogeneity.Medicine, Faculty ofGraduat