title: 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-beta, TNF-alpha, 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.affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Yunping
authors.initials: Y
authors.lastname: Luo
authors.forename: He
authors.initials: H
authors.lastname: Zhou
authors.forename: Jörg
authors.initials: J
authors.lastname: Krueger
authors.forename: Charles
authors.initials: C
authors.lastname: Kaplan
authors.forename: Sung-Hyung
authors.initials: SH
authors.lastname: Lee
authors.forename: Carrie
authors.initials: C
authors.lastname: Dolman
authors.forename: Dorothy
authors.initials: D
authors.lastname: Markowitz
authors.forename: Wenyuan
authors.initials: W
authors.lastname: Wu
authors.forename: Cheng
authors.initials: C
authors.lastname: Liu
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Reisfeld
authors.forename: Rong
authors.initials: R
authors.lastname: Xiang
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D018450:Disease Progression; D005260:Female; D007150:Immunohistochemistry; D008213:Lymphocyte Activation; D008264:Macrophages / Q000502:physiology*; D015674:Mammary Neoplasms, Animal / Q000276:immunology* / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D013601:T-Lymphocytes / Q000276:immunology