title: CDDO-Me Redirects Activation of Breast Tumor Associated Macrophages.
abstract: Tumor-associated macrophages can account for up to 50% of the tumor mass in breast cancer patients and high TAM density is associated with poor clinical prognosis. Because TAMs enhance tumor growth, development, and metastatic potential, redirection of TAM activation may have significant therapeutic benefit. Our studies in primary human macrophages and murine breast TAMs suggest that the synthetic oleanane triterpenoid CDDO-methyl ester (CDDO-Me) reprograms the activation profile of TAMs from tumor-promoting to tumor-inhibiting. We show that CDDO-Me treatment inhibits expression of IL-10 and VEGF in stimulated human M2 macrophages and TAMs but increases expression of TNF-α and IL-6. Surface expression of CD206 and CD163, which are characteristic of M2 activation, is significantly attenuated by CDDO-Me. In contrast, CDDO-Me up-regulates surface expression of HLA-DR and CD80, which are markers of M1 activation, and importantly potentiates macrophage activation of autologous T cells but inhibits endothelial cell vascularization. These results show for the first time that CDDO-Me redirects activation of M2 macrophages and TAMs from immune-suppressive to immune-stimulatory, and implicate a role for CDDO-Me as an immunotherapeutic in the treatment of breast and potentially other types of cancer.
authors.affiliation: Department of Obstetrics and Gynecology, Geisel School of Medicine, Lebanon, New Hampshire, United States of America.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Ball
authors.affiliation: Department of Obstetrics and Gynecology, Geisel School of Medicine, Lebanon, New Hampshire, United States of America.
authors.forename: Emilie P
authors.initials: EP
authors.lastname: Shipman
authors.affiliation: Department of Obstetrics and Gynecology, Geisel School of Medicine, Lebanon, New Hampshire, United States of America.
authors.forename: Hyunjung
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine, Hanover, New Hampshire, United States of America.
authors.forename: Karen T
authors.initials: KT
authors.lastname: Liby
authors.affiliation: Department of Obstetrics and Gynecology, Geisel School of Medicine, Lebanon, New Hampshire, United States of America.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Pioli
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology
chemical_list: D014408:Biomarkers, Tumor; D016207:Cytokines; D012333:RNA, Messenger; D009828:Oleanolic Acid; C445068:bardoxolone methyl