Macropinocytosis of Nab-paclitaxel Drives Macrophage Activation in Pancreatic Cancer

作者：Cullis Jane; Siolas Despina; Avanzi Antonina; Barui Sugata; Maitra Anirban; Bar Sagi Dafna^*

来源：Cancer Immunology Research, 2017, 5(3): 182-190.

DOI：10.1158/2326-6066.CIR-16-0125

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. Nabpaclitaxel (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. Here, we show that macrophages internalized nab-paclitaxel via macropinocytosis. The macropinocytic uptake of nab-paclitaxel induced macrophage immunostimulatory (M1) cytokine expression and synergized with IFN gamma to promote inducible nitric oxide synthase expression in a TLR4-dependent manner. Nab-paclitaxel was internalized by tumor-associated macrophages in vivo, and therapeutic doses of nab-paclitaxel alone, and in combination with gemcitabine, increased the MHCII(+)CD80(+)CD86(+) M1 macrophage population. These data revealed an unanticipated role for nab-paclitaxel in macrophage activation and rationalized its potential use to target immune evasion in pancreatic cancer.

• 出版日期2017-3