title: SCS macrophages suppress melanoma by restricting tumor-derived vesicle-B cell interactions.
abstract: 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.
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Pucci
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA. Graduate Program in Immunology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Garris
authors.affiliation: Department of Neurology, Massachusetts General Hospital Research Institute, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Charles P
authors.initials: CP
authors.lastname: Lai
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Andita
authors.initials: A
authors.lastname: Newton
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Pfirschke
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA. Graduate Program in Immunology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Camilla
authors.initials: C
authors.lastname: Engblom
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: David
authors.initials: D
authors.lastname: Alvarez
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Sprachman
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA. Graduate Program in Immunology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Evavold
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Magnuson
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ulrich H
authors.initials: UH
authors.lastname: von Andrian
authors.affiliation: Institute of Pathology, University Hospital Basel, 4031 Basel, Switzerland.
authors.forename: Katharina
authors.initials: K
authors.lastname: Glatz
authors.affiliation: Department of Neurology, Massachusetts General Hospital Research Institute, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Xandra O
authors.initials: XO
authors.lastname: Breakefield
authors.affiliation: Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital Research Institute, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Thorsten R
authors.initials: TR
authors.lastname: Mempel
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA. mpittet@mgh.harvard.edu.
authors.forename: Mikael J
authors.initials: MJ
authors.lastname: Pittet
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000648:ultrastructure; D002450:Cell Communication; D000067128:Extracellular Vesicles / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D008198:Lymph Nodes / Q000276:immunology; D042601:Lymphatic Vessels / Q000276:immunology; D008264:Macrophages / Q000737:chemistry / Q000276:immunology*; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D063267:Sialic Acid Binding Ig-like Lectin 1 / Q000032:analysis / Q000276:immunology; D012878:Skin Neoplasms / Q000276:immunology* / Q000473:pathology
chemical_list: D063267:Sialic Acid Binding Ig-like Lectin 1