title: Tumor-Associated Macrophages Suppress the Cytotoxic Activity of Antimitotic Agents.
abstract: Antimitotic agents, including Taxol, disrupt microtubule dynamics and cause a protracted mitotic arrest and subsequent cell death. Despite the broad utility of these drugs in breast cancer and other tumor types, clinical response remains variable. Tumor-associated macrophages (TAMs) suppress the duration of Taxol-induced mitotic arrest in breast cancer cells and promote earlier mitotic slippage. This correlates with a decrease in the phosphorylated form of histone H2AX (γH2AX), decreased p53 activation, and reduced cancer cell death in interphase. TAMs promote cancer cell viability following mitotic slippage in a manner sensitive to MAPK/ERK kinase (MEK) inhibition. Acute depletion of major histocompatibility complex class II low (MHCIIlo) TAMs increased Taxol-induced DNA damage and apoptosis in cancer cells, leading to greater efficacy in intervention trials. MEK inhibition blocked the protective capacity of TAMs and phenocopied the effects of TAM depletion on Taxol treatment. TAMs suppress the cytotoxic effects of Taxol, in part through cell non-autonomous modulation of mitotic arrest in cancer cells, and targeting TAM-cancer cell interactions potentiates Taxol efficacy.
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Oakley C
authors.initials: OC
authors.lastname: Olson
authors.affiliation: Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Hyunjung
authors.initials: H
authors.lastname: Kim
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Daniela F
authors.initials: DF
authors.lastname: Quail
authors.affiliation: Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Foley
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Ludwig Institute for Cancer Research, University of Lausanne, 1066 Lausanne, Switzerland; Department of Oncology, University of Lausanne, 1066 Lausanne, Switzerland. Electronic address: johanna@joycelab.org.
authors.forename: Johanna A
authors.initials: JA
authors.lastname: Joyce
mesh_terms: D000818:Animals; D050256:Antimitotic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D052160:Benzothiazoles / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy; D002470:Cell Survival / Q000187:drug effects*; D004249:DNA Damage; D042783:Endothelial Cells / Q000187:drug effects; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D008285:Major Histocompatibility Complex; D051379:Mice; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases; D008938:Mitosis / Q000187:drug effects*; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use; D010848:Picolinic Acids / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C568289:4-(2-(2-hydroxycyclohexylamino)benzothiazol-6-yloxy)pyridine-2-carboxylic acid methylamide; D050256:Antimitotic Agents; D052160:Benzothiazoles; C468783:H2AX protein, human; D006657:Histones; D010848:Picolinic Acids; D016159:Tumor Suppressor Protein p53; D020929:Mitogen-Activated Protein Kinase Kinases; D017239:Paclitaxel
keywords: Taxol; antimitotic; breast cancer; chemoresistance; chemotherapy; macrophage; microenvironment; mitotic arrest; mitotic slippage; tetraploid