TY - JOUR
T1 - SCS macrophages suppress melanoma by restricting tumor-derived vesicle-B cell interactions
AU - Pucci, Ferdinando
AU - Garris, Christopher
AU - Lai, Charles P.
AU - Newton, Andita
AU - Pfirschke, Christina
AU - Engblom, Camilla
AU - Alvarez, David
AU - Sprachman, Melissa
AU - Evavold, Charles
AU - Magnuson, Angela
AU - Von Andrian, Ulrich H.
AU - Glatz, Katharina
AU - Breakefield, Xandra O.
AU - Mempel, Thorsten R.
AU - Weissleder, Ralph
AU - Pittet, Mikael J.
N1 - Funding Information:
We thank M. Ericsson for helping with electron microscopy studies, T. Murooka for multiphoton microscopy experiments, and S. Mordecai for imaging flow cytometry. The data presented in this manuscript are tabulated in the main paper and in the supplementary materials. Supported by the Samana Cay MGH Research Scholar Fund and NIH grants R21-CA190344, P50-CA86355, and R01-AI084880 (M.J.P.); NIH grants U54-CA126515, T32CA79443, RO1EB010011, 1R01CA164448, and 1R33CA202064 (R.W.); NIH grant P01-CA069246 (X.O.B. and R.W.); NIH grant U19 CA179563 (X.O.B. and T.R.M.); NIH grant R01 AI097052 (T.R.M.); NIH grant F31-CA196035 (CG.); an EMBO long-term fellowship and an MGH ECOR Funds for Medical Discovery Fellowship (F.P.); Deutsche Forschungsgemeinschaft grant PF809/1-1 (C.P.); a Canadian Institutes of Health Research postdoctoral fellowship (C.P.L.); and Boehringer Ingelheim Funds (CE.).
PY - 2016/4/8
Y1 - 2016/4/8
N2 - Tumor-derived extracellular vesicles (tEVs) are important signals in tumor-host cell communication, yet it remains unclear how endogenously produced tEVs affect the host in different areas of the body. We combined imaging and genetic analysis to track melanoma-derived vesicles at organismal, cellular, and molecular scales to show that endogenous tEVs efficiently disseminate via lymphatics and preferentially bind subcapsular sinus (SCS) CD169+ macrophages in tumor-draining lymph nodes (tdLNs) in mice and humans. The CD169+ macrophage layer physically blocks tEV dissemination but is undermined during tumor progression and by therapeutic agents. A disrupted SCS macrophage barrier enables tEVs to enter the lymph node cortex, interact with B cells, and foster tumor-promoting humoral immunity. Thus, CD169+ macrophages may act as tumor suppressors by containing tEV spread and ensuing cancer-enhancing immunity.
AB - Tumor-derived extracellular vesicles (tEVs) are important signals in tumor-host cell communication, yet it remains unclear how endogenously produced tEVs affect the host in different areas of the body. We combined imaging and genetic analysis to track melanoma-derived vesicles at organismal, cellular, and molecular scales to show that endogenous tEVs efficiently disseminate via lymphatics and preferentially bind subcapsular sinus (SCS) CD169+ macrophages in tumor-draining lymph nodes (tdLNs) in mice and humans. The CD169+ macrophage layer physically blocks tEV dissemination but is undermined during tumor progression and by therapeutic agents. A disrupted SCS macrophage barrier enables tEVs to enter the lymph node cortex, interact with B cells, and foster tumor-promoting humoral immunity. Thus, CD169+ macrophages may act as tumor suppressors by containing tEV spread and ensuing cancer-enhancing immunity.
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U2 - 10.1126/science.aaf1328
DO - 10.1126/science.aaf1328
M3 - Article
C2 - 26989197
AN - SCOPUS:84961390149
SN - 0036-8075
VL - 352
SP - 242
EP - 246
JO - Science
JF - Science
IS - 6282
ER -