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 brain1-3.,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.
Limited adjuvant treatment options exist for patients with high-risk surgically resected melanoma.,This first-in-human study investigated the safety, tolerability and immunologic correlates of Melanoma GVAX, a lethally irradiated granulocyte-macrophage colony stimulating factor (GM-CSF)-secreting allogeneic whole-cell melanoma vaccine, administered in the adjuvant setting.,Patients with stage IIB-IV melanoma were enrolled following complete surgical resection.,Melanoma GVAX was administered intradermally once every 28 days for four cycles, at 5E7 cells/cycle (n = 3), 2E8 cells/cycle (n = 9), or 2E8 cells/cycle preceded by cyclophosphamide 200 mg/m2 to deplete T regulatory cells (Tregs; n = 8).,Blood was collected before each vaccination and at 4 and 6 months after treatment initiation for immunologic studies.,Vaccine injection site biopsies and additional blood samples were obtained 2 days after the 1st and 4th vaccines.,Among 20 treated patients, 18 completed 4 vaccinations.,Minimal treatment-related toxicity was observed.,One patient developed vitiligo and patches of white hair during the treatment and follow-up period.,Vaccine site biopsies demonstrated complex inflammatory infiltrates, including significant increases in eosinophils and PD-1+ lymphocytes from cycle 1 to cycle 4 (P < 0.05).,Serum GM-CSF concentrations increased significantly in a dose-dependent manner 48 h after vaccination (P = 0.0086), accompanied by increased numbers of activated circulating monocytes (P < 0.0001) and decreased percentages of myeloid-derived suppressor cells among monocytes (CD14+ , CD11b+ , HLA-DR low or negative; P = 0.002).,Cyclophosphamide did not affect numbers of circulating Tregs.,No significant changes in anti-melanoma immunity were observed in peripheral T cells by interferon-gamma ELIPSOT, or immunoglobulins by serum Western blotting.,Melanoma GVAX was safe and tolerable in the adjuvant setting.,Pharmacodynamic testing revealed complex vaccine site immune infiltrates and an immune-reactive profile in circulating monocytic cell subsets.,These findings support the optimization of Melanoma GVAX with additional monocyte and dendritic cell activators, and the potential development of combinatorial treatment regimens with synergistic agents.,Trial registration: NCT01435499,The online version of this article (doi:10.1186/s12967-015-0572-3) contains supplementary material, which is available to authorized users.