Tumor-associated macrophages promote invasion while retaining Fc-dependent anti-tumor function.

Grugan KD, McCabe FL, Kinder M, Greenplate AR, Harman BC, Ekert JE, van Rooijen N, Anderson GM, Nemeth JA, Strohl WR, Jordan RE, Brezski RJ
J Immunol. 2012 189 (11): 5457-66

PMID: 23105143 · DOI:10.4049/jimmunol.1201889

Tumor-associated macrophages (TAMs) have been shown to promote tumor progression, and increased TAM infiltration often correlates with poor prognosis. However, questions remain regarding the phenotype of macrophages within the tumor and their role in mAb-dependent cytotoxicity. This study demonstrates that whereas TAMs have protumor properties, they maintain Fc-dependent anti-tumor function. CD11b(+)CD14(+) TAMs isolated from primary human breast tumors expressed activating FcγRs. To model breast cancer TAMs in vitro, conditioned medium from breast cancer cells was used to drive human peripheral monocyte differentiation into macrophages. Tumor-conditioned macrophages were compared with in vitro derived M1 and M2a macrophages and were found to promote tumor cell invasion and express M2a markers, confirming their protumor potential. However, unlike M2a macrophages, tumor-conditioned macrophages expressed FcγRs and phagocytosed tumor cells in the presence of a tumor Ag-targeting mAb, unmasking an underappreciated tumoricidal capacity of TAMs. In vivo macrophage depletion reduced the efficacy of anti-CD142 against MDA-MB-231 xenograft growth and metastasis in SCID/beige mice, implicating a critical role for macrophages in Fc-dependent cell killing. M-CSF was identified in tumor-conditioned media and shown to be capable of differentiating macrophages with both pro- and anti-tumor properties. These results highlight the plasticity of TAMs, which are capable of promoting tumor progression and invasion while still retaining tumoricidal function in the presence of tumor-targeting mAbs.

MeSH Terms (22)

Animals Antibodies, Neoplasm Antigens, Neoplasm Breast Neoplasms CD11b Antigen Cell Movement Cell Proliferation Culture Media, Conditioned Disease Progression Female Humans Immunophenotyping Lipopolysaccharide Receptors Macrophage Colony-Stimulating Factor Macrophages Mice Mice, SCID Neoplasm Invasiveness Neoplasm Transplantation Phagocytosis Primary Cell Culture Receptors, IgG

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