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.
Highlights
Breast cancer is the most commonly diagnosed non-skin cancer among women worldwide and is the second leading cause of cancer death among women [1, 2]
This study demonstrates for the first time that the synthetic triterpenoid CDDO-methyl ester (CDDO-Me) markedly attenuates the immunosuppressive activation state of primary breast Tumor associated macrophages (TAMs), inhibiting both RNA and protein expression of tumor-promoting IL-10 and VEGF, while enhancing expression of immune-stimulatory TNF-α, IFN-γ, and IL-6
Because we have shown that CDDO-Me mediates these effects in M2-skewed macrophages that recapitulate TAM activation, we believe this drug may modulate TAM polarization in other types of cancer as well
Summary
Breast cancer is the most commonly diagnosed non-skin cancer among women worldwide and is the second leading cause of cancer death among women [1, 2]. Early detection and chemotherapeutic treatments have contributed to recent modest declines in breast cancer mortality, the incidence of estrogen receptor negative (ER-) breast cancer has not changed significantly in over 30 years and ~40,000 women succumb to breast cancer each year [1]. There is clearly a pressing need for the development of new, innovative and aggressive approaches to combat this insidious disease. Numerous studies demonstrate that tumor tissue microenvironments are distinct and consist of malignant as well as non-malignant cell types [3]. Tumor associated macrophages (TAMs) can constitute up to 50% of the tumor mass [3, 4], and high TAM density is correlated
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