Macropinocytosis of Nab-paclitaxel Drives Macrophage Activation in Pancreatic Cancer.
Abstact
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 <i>in vivo</i>, and therapeutic doses of nab-paclitaxel alone, and in combination with gemcitabine, increased the MHCII<sup>+</sup>CD80<sup>+</sup>CD86<sup>+</sup> 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. <i>Cancer Immunol Res; 5(3); 182-90. ©2017 AACR</i>.
Authors
- Avanzi A
- Bar-Sagi D
- Barui S
- Cullis J
- Maitra A
- Siolas D