title: Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer.
abstract: The microenvironment is known to critically modulate tumor progression, yet its role in regulating treatment response is poorly understood. Here we found increased macrophage infiltration and cathepsin protease levels in mammary tumors following paclitaxel (Taxol) chemotherapy. Cathepsin-expressing macrophages protected against Taxol-induced tumor cell death in coculture, an effect fully reversed by cathepsin inhibition and mediated partially by cathepsins B and S. Macrophages were also found to protect against tumor cell death induced by additional chemotherapeutics, specifically etoposide and doxorubicin. Combining Taxol with cathepsin inhibition in vivo significantly enhanced efficacy against primary and metastatic tumors, supporting the therapeutic relevance of this effect. Additionally incorporating continuous low-dose cyclophosphamide dramatically impaired tumor growth and metastasis and improved survival. This study highlights the importance of integrated targeting of the tumor and its microenvironment and implicates macrophages and cathepsins in blunting chemotherapeutic response.
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Tanaya
authors.initials: T
authors.lastname: Shree
authors.forename: Oakley C
authors.initials: OC
authors.lastname: Olson
authors.forename: Benelita T
authors.initials: BT
authors.lastname: Elie
authors.forename: Jemila C
authors.initials: JC
authors.lastname: Kester
authors.forename: Alfred L
authors.initials: AL
authors.lastname: Garfall
authors.forename: Kenishana
authors.initials: K
authors.lastname: Simpson
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Bell-McGuinn
authors.forename: Emily C
authors.initials: EC
authors.lastname: Zabor
authors.forename: Edi
authors.initials: E
authors.lastname: Brogi
authors.forename: Johanna A
authors.initials: JA
authors.lastname: Joyce
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002403:Cathepsins / Q000378:metabolism*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008264:Macrophages / Q000473:pathology*; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009361:Neoplasm Invasiveness; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D005047:Etoposide; D004317:Doxorubicin; D002403:Cathepsins; D017239:Paclitaxel