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 2

Targeting of legumain-expressing cells results in suppression of tumor progression.

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Targeting of legumain-expressing cells results in suppression of tumor p...
(A) Schematic of DNA vaccines constructed with the pCMV/myc/cyto vector backbone where the legumain gene was fused to the C terminal of mutant polyubiquitin. The entire fragment was inserted, and protein expression was demonstrated by Western blotting. Mu-legumain, murine legumain. (B) Prophylactic model: The vaccination schedule was designed for 3 immunizations at 1-week intervals followed by an i.v. challenge with 2 × 105 D121 non–small cell lung cancer cells and 5 × 104 CT26 colon cancer cells and mammary fat pad injection with 7 × 103 4T1 breast cancer cells. Lung weights were determined 24 days (D121 or CT26) or 30 days (4T1) after tumor cell challenge and analyzed in each group. Differences between the 2 control groups (PBS and/or empty vector) and the treatment group were statistically significant; **P < 0.005. Pre-challenge lung weight, 0.2 g. (C) Therapeutic model: Groups of BALB/c mice (n = 8) were initially injected in the mammary fat pad with 7 × 103 4T1 breast cancer cells and thereafter vaccinated 3 times on days 3, 7, and 11 with PBS, empty vector, or the pLegumain vaccine, respectively, and primary tumors excised on day 12. Survival plots represent results for 8 mice in each of the treatment and control groups. The difference between the empty vector control group and the treatment group was statistically significant; **P < 0.005.