VEGF-C-driven lymphatic drainage enables brain tumor immunosurveillance

Immune surveillance against pathogens and tumors in the central nervous system (CNS) is thought to be limited due to the lack of lymphatic drainage. However, recent characterization of the meningeal lymphatic network sheds new light on previously unappreciated ways of eliciting immune response to antigens expressed in the brain(1–3). Despite the remarkable progress made in our understanding of the development and structure of meningeal lymphatics, its contribution in evoking a protective antigen-specific immune response in the brain still remains unclear. Here we examine whether meningeal lymphatic vasculature can be manipulated to mount better immune responses against brain tumors. Using a mouse model of glioblastoma multiforme (GBM), we show that very limited CD8 T cell immunity to GBM antigen is elicited when the tumor is confined to the CNS, resulting in uncontrolled tumor growth. However, ectopic VEGF-C expression promotes enhanced CD8 T cell priming in the draining deep cervical lymph nodes, migration of CD8 T cells into the tumor and rapid clearance of the GBM, resulting in long-lasting antitumor memory response. Further, VEGF-C mRNA works synergistically with checkpoint blockade therapy to eradicate existing GBM. These results reveal the capacity of VEGF-C to promote tumor immune surveillance, and offer a new therapeutic approach to treat brain tumors.