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Macropinocytosis of Nab-paclitaxel Drives Macrophage Activation in Pancreatic Cancer
Jane Cullis1, Despina Siolas1, Antonina Avanzi1
1Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York.
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.
Insights
Nab-paclitaxel activates immunosuppressive macrophages in pancreatic cancer, shifting them to an immunostimulatory M1 state. This unexpected finding suggests nab-paclitaxel can help overcome immune evasion in pancreatic ductal adenocarcinoma treatment.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Pancreatic cancer exhibits resistance to treatments, partly due to immunosuppressive M2 macrophages within the tumor stroma.
- Nab-paclitaxel (Abraxane), combined with gemcitabine, is a standard first-line therapy for pancreatic cancer.
Purpose of the Study:
- To investigate the mechanism by which nab-paclitaxel interacts with macrophages in pancreatic cancer.
- To determine if nab-paclitaxel can alter the immunosuppressive phenotype of tumor-associated macrophages.
Main Methods:
- Macrophages were studied for nab-paclitaxel internalization via macropinocytosis.
- Macrophage cytokine expression and M1 polarization markers (MHCII, CD80, CD86) were analyzed.
- In vivo studies assessed nab-paclitaxel's effect on tumor-associated macrophages.
Main Results:
- Macrophages internalized nab-paclitaxel through macropinocytosis.
- Nab-paclitaxel induced M1 cytokine expression and promoted inducible nitric oxide synthase in a TLR4-dependent manner.
- Therapeutic doses of nab-paclitaxel increased M1 macrophage populations in vivo, alone and with gemcitabine.
Conclusions:
- Nab-paclitaxel unexpectedly activates macrophages, promoting an immunostimulatory M1 phenotype.
- This macrophage activation by nab-paclitaxel offers a potential strategy to target immune evasion in pancreatic cancer.
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