RESUMO
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.
Assuntos
Neoplasias da Mama/imunologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Ácido Oleanólico/análogos & derivados , Animais , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Citocinas/genética , Citocinas/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Macrófagos/citologia , Macrófagos/metabolismo , Camundongos , Ácido Oleanólico/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Linfócitos T/citologiaRESUMO
PROBLEM: Human uterine macrophages must maintain an environment hospitable to implantation and pregnancy and simultaneously provide protection against pathogens. Although macrophages comprise a significant portion of leukocytes within the uterine endometrium, the activation profile and functional response of these cells to endotoxin are unknown. METHOD OF STUDY: Flow cytometric analysis of surface receptors and intracellular markers expressed by macrophages isolated from human endometria was performed. Uterine macrophages were stimulated with LPS. Cytokines, chemokines, and growth factors expressed by these cells were analyzed using Bio-Plex analysis. RESULTS: CD163(high) human endometrial macrophages constitutively secrete both pro- and anti-inflammatory cytokines as well as pro-angiogenic factors and secretion of these factors is LPS-inducible. CONCLUSION: A major population of human uterine macrophages is alternatively activated. These cells secrete factors in response to LPS that are involved in the activation of immune responses and tissue homeostasis.