title: VEGF-C promotes immune tolerance in B16 melanomas and cross-presentation of tumor antigen by lymph node lymphatics.
abstract: Tumor expression of the lymphangiogenic factor VEGF-C is correlated with metastasis and poor prognosis, and although VEGF-C enhances transport to the draining lymph node (dLN) and antigen exposure to the adaptive immune system, its role in tumor immunity remains unexplored. Here, we demonstrate that VEGF-C promotes immune tolerance in murine melanoma. In B16 F10 melanomas expressing a foreign antigen (OVA), VEGF-C protected tumors against preexisting antitumor immunity and promoted local deletion of OVA-specific CD8(+) T cells. Naive OVA-specific CD8(+) T cells, transferred into tumor-bearing mice, were dysfunctionally activated and apoptotic. Lymphatic endothelial cells (LECs) in dLNs cross-presented OVA, and naive LECs scavenge and cross-present OVA in vitro. Cross-presenting LECs drove the proliferation and apoptosis of OVA-specific CD8(+) T cells ex vivo. Our findings introduce a tumor-promoting role for lymphatics in the tumor and dLN and suggest that lymphatic endothelium in the local microenvironment may be a target for immunomodulation.
authors: Institute of Bioengineering (IBI), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland.
authors: Amanda W
authors: AW
authors: Lund
authors: Fernanda V
authors: FV
authors: Duraes
authors: Sachiko
authors: S
authors: Hirosue
authors: Vidya R
authors: VR
authors: Raghavan
authors: Chiara
authors: C
authors: Nembrini
authors: Susan N
authors: SN
authors: Thomas
authors: Amine
authors: A
authors: Issa
authors: Stéphanie
authors: S
authors: Hugues
authors: Melody A
authors: MA
authors: Swartz
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology; D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D042783:Endothelial Cells / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology* / Q000473:pathology; D042583:Lymphangiogenesis; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D009362:Neoplasm Metastasis; D010455:Peptides / Q000276:immunology; D017154:Stromal Cells / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D015395:Histocompatibility Antigens Class I; D010455:Peptides; D042582:Vascular Endothelial Growth Factor C