VEGF-C Promotes Immune Tolerance in B16 Melanomas and Cross-Presentation of Tumor Antigen by Lymph Node Lymphatics

SummaryTumor 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.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► VEGF-C protects tumors from preinduced vaccine immunity ► VEGF-C enhances dysfunctional activation of CD8 T cells in tumor-draining lymph nodes ► Lymph node lymphatic endothelial cells scavenge and cross-present tumor antigen ► Lymphatic endothelial cells cross-tolerize antigen-specific CD8 T cells ex vivo