Behavior of endogenous tumor-associated macrophages assessed in vivo using a functionalized nanoparticle.
Tumor-associated macrophages (TAMs) invade the tumor stroma in many cancers, yet their role is incompletely understood. To visualize and better understand these critical cells in tumor progression, we screened a portfolio of rationally selected, injectable agents to image endogenous TAMs ubiquitously in three different cancer models (colon carcinoma, lung adenocarcinoma, and soft tissue sarcoma). AMTA680, a functionally derivatized magneto-fluorescent nanoparticle, labeled a subset of myeloid cells with an "M2" macrophage phenotype, whereas other neighboring cells, including tumor cells and a variety of other leukocytes, remained unlabeled. We further show that AMTA680-labeled endogenous TAMs are not altered and can be tracked noninvasively at different resolutions and using various imaging modalities, e.g., fluorescence molecular tomography, magnetic resonance imaging, and multiphoton and confocal intravital microscopy. Quantitative assessment of TAM distribution and activity in vivo identified that these cells cluster in delimited foci within tumors, show relatively low motility, and extend cytoplasmic protrusions for prolonged physical interactions with neighboring tumor cells. Noninvasive imaging can also be used to monitor TAM-depleting regimen quantitatively. Thus, AMTA680 or related cell-targeting agents represent appropriate injectable vehicles for in vivo analysis of the tumor microenvironment.
Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Antoine
A
Leimgruber
Cedric
C
Berger
Virna
V
Cortez-Retamozo
Martin
M
Etzrodt
Andita P
AP
Newton
Peter
P
Waterman
Jose Luiz
JL
Figueiredo
Rainer H
RH
Kohler
Natalie
N
Elpek
Thorsten R
TR
Mempel
Filip K
FK
Swirski
Matthias
M
Nahrendorf
Ralph
R
Weissleder
Mikael J
MJ
Pittet
D000818:Animals; D003952:Diagnostic Imaging / Q000379:methods*; D007150:Immunohistochemistry; D008264:Macrophages / Q000166:cytology*; D008279:Magnetic Resonance Imaging; D053768:Metal Nanoparticles; D051379:Mice; D018613:Microscopy, Confocal; D009369:Neoplasms / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction