Intravital imaging reveals distinct responses of depleting dynamic tumor-associated macrophage and dendritic cell subpopulations.
Tumor-infiltrating inflammatory cells comprise a major part of the stromal microenvironment and support cancer progression by multiple mechanisms. High numbers of tumor myeloid cells correlate with poor prognosis in breast cancer and are coupled with the angiogenic switch and malignant progression. However, the specific roles and regulation of heterogeneous tumor myeloid populations are incompletely understood. CSF-1 is a major myeloid cell mitogen, and signaling through its receptor CSF-1R is also linked to poor outcomes. To characterize myeloid cell function in tumors, we combined confocal intravital microscopy with depletion of CSF-1R-dependent cells using a neutralizing CSF-1R antibody in the mouse mammary tumor virus long-terminal region-driven polyoma middle T antigen breast cancer model. The depleted cells shared markers of tumor-associated macrophages and dendritic cells (M-DCs), matching the phenotype of tumor dendritic cells that take up antigens and interact with T cells. We defined functional subgroups within the M-DC population by imaging endocytic and matrix metalloproteinase activity. Anti-CSF-1R treatment altered stromal dynamics and impaired both survival of M-DCs and accumulation of new M-DCs, but did not deplete Gr-1(+) neutrophils or block doxorubicin-induced myeloid cell recruitment, and had a minimal effect on lung myeloid cells. Nevertheless, prolonged treatment led to delayed tumor growth, reduced vascularity, and decreased lung metastasis. Because the myeloid infiltrate in metastatic lungs differed significantly from that in mammary tumors, the reduction in metastasis may result from the impact on primary tumors. The combination of functional analysis by intravital imaging with cellular characterization has refined our understanding of the effects of experimental targeted therapies on the tumor microenvironment.
Department of Anatomy, University of California, San Francisco, CA 94143; and.
Marja
M
Lohela
Department of Anatomy, University of California, San Francisco, CA 94143; and.
Amy-Jo
AJ
Casbon
Department of Anatomy, University of California, San Francisco, CA 94143; and.
Aleksandra
A
Olow
Amgen Corporation, Seattle, WA 98119.
Lynn
L
Bonham
Amgen Corporation, Seattle, WA 98119.
Daniel
D
Branstetter
Amgen Corporation, Seattle, WA 98119.
Ning
N
Weng
Amgen Corporation, Seattle, WA 98119.
Jeffrey
J
Smith
Department of Anatomy, University of California, San Francisco, CA 94143; and zena.werb@ucsf.edu.
Zena
Z
Werb
D000818:Animals; D002455:Cell Division; D004705:Endocytosis; D005260:Female; D008175:Lung Neoplasms / Q000556:secondary; D008264:Macrophages / Q000276:immunology*; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000473:pathology*; D051379:Mice; D009504:Neutrophils / Q000276:immunology; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000276:immunology; D059016:Tumor Microenvironment
D016186:Receptor, Macrophage Colony-Stimulating Factor
CSF-1 receptor; inflammation; lung metastasis; matrix metalloproteinase; myeloid cells