Macropinocytosis of Nab-paclitaxel Drives Macrophage Activation in Pancreatic Cancer.

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.

journal_name

Cancer Immunol Res

authors

Cullis J,Siolas D,Avanzi A,Barui S,Maitra A,Bar-Sagi D

doi

10.1158/2326-6066.CIR-16-0125

subject

Has Abstract

pub_date

2017-03-01 00:00:00

pages

182-190

issue

3

eissn

2326-6066

issn

2326-6074

pii

2326-6066.CIR-16-0125

journal_volume

5

pub_type

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