Title: Harnessing Macrophage Macropinocytosis as a Therapeutic Strategy in Pancreatic Cancer
Pancreatic cancer is a devastating disease that is largely refractory to currently available treatment strategies. Therapeutic resistance is partially attributed to the dense stromal reaction of pancreatic ductal adenocarcinoma tumors that includes a pervasive infiltration of immunosuppressive (M2) macrophages. Nab-paclitaxel (trade name Abraxane) is a nanoparticle albumin-bound formulation of paclitaxel that, in combination with gemcitabine, is currently the first-line treatment for pancreatic cancer. We show that macrophages internalize high levels of nab-paclitaxel via macropinocytosis. The macropinocytic uptake of nab-paclitaxel induces macrophage immunostimulatory (M1) activation in vitro and in an orthotopic model of pancreatic cancer. These data reveal an unanticipated role for nab-paclitaxel in macrophage activation and rationalize the development of albumin-coupled immunostimulatory agents to effectively target and re-polarize macrophages in pancreatic cancer.
Host: David Meiri