title: 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 macrophagesin 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.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York.
authors.forename: Jane
authors.initials: J
authors.lastname: Cullis
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York.
authors.forename: Despina
authors.initials: D
authors.lastname: Siolas
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York.
authors.forename: Antonina
authors.initials: A
authors.lastname: Avanzi
authors.affiliation: Departments of Pathology and Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Sugata
authors.initials: S
authors.lastname: Barui
authors.affiliation: Departments of Pathology and Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York. dafna.bar-sagi@nyumc.org.
authors.forename: Dafna
authors.initials: D
authors.lastname: Bar-Sagi
mesh_terms: D000418:Albumins / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008262:Macrophage Activation / Q000187:drug effects* / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D010873:Pinocytosis / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D000970:Antineoplastic Agents; D051197:Toll-Like Receptor 4; D017239:Paclitaxel