Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy that has no effective treatment. The tumor microenvironment (TME) of PDA employs a multitude of immune derangement strategies to protect PDA from immune elimination. Tumor associated macrophages (TAMs) have been implicated in pathogenesis of immune suppression of PDA-TME, however, its underlying mechanisms remained largely unknown. Using primary patient samples, our studies showed that in comparison with macrophages isolated from normal pancreatic tissues, the phagocytosis activity of PDA-TAM is significantly reduced. We found that the expression of homeobox protein VentX, a master regulator of macrophage plasticity, is significantly decreased in the PDA-TAMs. We demonstrated that VentX is required for phagocytosis and that restoration of VentX expression in PDA-TAMs promotes phagocytosis through regulating the signaling cascades involved in the process. Using an ex-vivo culture model of primary human PDA, we showed that VentX-modulated-TAMs transformed PDA-TME from a pro-tumor milieu to an anti-tumor microenvironment by rectifying differentiation, proliferation and activation of PDA-infiltrating immune cells. Using NSG-PDX models of primary human PDAs, we showed that VentX-modulated-TAMs exert strong inhibition on PDA tumorigenesis in vivo. Taken together, our data revealed a central mechanism underlying immune evasion of PDA and a potential novel venue to improve PDA prognosis.
Yi Le, Hong Gao, William G. Richards, Lei Zhao, Ronald Bleday, Thomas Clancy, Zhenglun Zhu