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Targeting tumor-associated macrophages as a novel strategy against breast cancer
Yunping Luo, … , Ralph A. Reisfeld, Rong Xiang
Yunping Luo, … , Ralph A. Reisfeld, Rong Xiang
Published August 1, 2006
Citation Information: J Clin Invest. 2006;116(8):2132-2141. https://doi.org/10.1172/JCI27648.
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Research Article Oncology Article has an altmetric score of 9

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

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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 4

MHC class I antigen–restricted specific CD8+ T cell response against legumain-expressing cells.

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                  MHC class I antigen–restricted specific CD8+
        ...
(A) DNA vaccination enhances expression of costimulatory molecules by DCs. Lymphocytes from Peyer’s patches obtained 3 days after vaccination were stained with FITC-labeled anti-CD11cAb in combination with PE-conjugated anti-CD80, anti–MHC class I, or anti-CD40 Abs. *P < 0.05 compared with control groups. (B) Intracytoplasmic IFN-γ release of CD8+ T cells was measured by FACS analysis. **P < 0.005 compared with control groups. (C) Production of specific IFN-γ was verified at the single-cell level by ELISPOT. This is indicated for lymphocytes from immunized mice restimulated with either legumain+ 4T1 tumor tissue cells or legumain– 4T1 cells, as indicated by the number of immunospots formed per well. **P < 0.005 compared with treatment group without stimulation; ##P < 0.005 compared with control groups. (D) Splenocytes isolated from treated mice were effective in killing TAMs according to a 51Cr release assay (#P < 0.01 compared with control groups). Inhibition experiments with Abs against H-2Kd/H-2Dd MHC class I antigens showed that T cell–mediated tumor cell lysis was MHC class I antigen restricted. Furthermore, in vivo depletions of CD4+ or CD8+ T cells indicated that lymphocytes isolated from vaccinated mice, which were thereafter depleted of CD8+ T cells, failed to induce cytotoxic killing of target cells. However, depletion of CD4+ T cells did not abrogate cytotoxic killing of these same target cells. #P < 0.01 compared with PBS or empty vector group.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 12 patents
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