Macropinocytosis of Nab-paclitaxel Drives Macrophage Activation in Pancreatic Cancer

Cancer Immunol Res. 2017 Mar;5(3):182-190. doi: 10.1158/2326-6066.CIR-16-0125. Epub 2017 Jan 20.

Abstract

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. 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 IFNγ 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. Cancer Immunol Res; 5(3); 182-90. ©2017 AACR.

MeSH terms

  • Albumins / pharmacology*
  • Albumins / therapeutic use
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Cell Line, Tumor
  • Disease Models, Animal
  • Female
  • Humans
  • Macrophage Activation / drug effects*
  • Macrophage Activation / immunology*
  • Macrophages / drug effects
  • Macrophages / immunology
  • Macrophages / metabolism
  • Paclitaxel / pharmacology*
  • Paclitaxel / therapeutic use
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / immunology*
  • Pancreatic Neoplasms / pathology*
  • Pinocytosis / immunology*
  • Toll-Like Receptor 4 / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • 130-nm albumin-bound paclitaxel
  • Albumins
  • Antineoplastic Agents
  • Toll-Like Receptor 4
  • Paclitaxel