Targeting tumor-associated macrophages as a novel strategy against breast cancer
Yunping Luo, He Zhou, Jörg Krueger, Charles Kaplan, Sung-Hyung Lee, Carrie Dolman, Dorothy Markowitz, Wenyuan Wu, Cheng Liu, Ralph A. Reisfeld, Rong Xiang
Yunping Luo, He Zhou, Jörg Krueger, Charles Kaplan, Sung-Hyung Lee, Carrie Dolman, Dorothy Markowitz, Wenyuan Wu, Cheng Liu, Ralph A. Reisfeld, Rong Xiang
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Research Article Oncology

Targeting tumor-associated macrophages as a novel strategy against breast cancer

Abstract

Tumor-associated macrophages (TAMs) are associated with tumor progression and metastasis. Here, we demonstrate for the first time that legumain, a member of the asparaginyl endopeptidase family functioning as a stress protein, overexpressed by TAMs, provides an ideal target molecule. In fact, a legumain-based DNA vaccine served as a tool to prove this point, as it induced a robust CD8+ T cell response against TAMs, which dramatically reduced their density in tumor tissues and resulted in a marked decrease in proangiogenic factors released by TAMs such as TGF-β, TNF-α, MMP-9, and VEGF. This, in turn, led to a suppression of both tumor angiogenesis and tumor growth and metastasis. Importantly, the success of this strategy was demonstrated in murine models of metastatic breast, colon, and non–small cell lung cancers, where 75% of vaccinated mice survived lethal tumor cell challenges and 62% were completely free of metastases. In conclusion, decreasing the number of TAMs in the tumor stroma effectively altered the tumor microenvironment involved in tumor angiogenesis and progression to markedly suppress tumor growth and metastasis. Gaining better insights into the mechanisms required for an effective intervention in tumor growth and metastasis may ultimately lead to new therapeutic targets and better anticancer strategies.

Authors

Yunping Luo, He Zhou, Jörg Krueger, Charles Kaplan, Sung-Hyung Lee, Carrie Dolman, Dorothy Markowitz, Wenyuan Wu, Cheng Liu, Ralph A. Reisfeld, Rong Xiang

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Figure 6

Elimination of TAMs results in a reduction in tumor angiogenesis.

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Elimination of TAMs results in a reduction in tumor angiogenesis. Suppre...
Suppression of VEGF-induced angiogenesis: BALB/c mice were vaccinated with empty vector, pLegumain, or pLegumain after either CD8+ or CD4+ T cell depletion in vivo. One week after the last vaccination, Matrigel was implanted s.c. into the midline of the abdomen of mice. Vascularization was induced by VEGF or bFGF. (A) The images were taken by a digital camera 6 days after Matrigel plug implantation. Additionally, the section of Matrigel plugs stained with Masson’s trichrome indicate blood vessel growth in Matrigel plugs, as indicated by arrows. Magnification, ×50. (B) Quantification of vessel growth was performed after in vivo staining of endothelium with FITC-labeled isolectin B4 and evaluation by fluorimetry. There was a decrease in the VEGF-induced neovasculature only after vaccination with the vector encoding legumain but not after vaccination with the empty vector or with pLegumain after depletion of CD8+ T cells. **P < 0.005, *P < 0.01 compared with the legumain treatment group. (C) Immunohistochemical staining was performed and evaluated by confocal microscopy. The cross-sections of Matrigel plugs were stained to determine the cell type that grew in or migrated into these plugs. The images indicate that endothelial cells with the CD31 marker or macrophages with the CD68 marker grew in or migrated into Matrigel plugs as indicated (magnification, ×350). H&E staining served as a control (magnification ×50).