Journal Article

VEGF-C-driven lymphatic drainage enables immunosurveillance of brain tumours

Bosenberg, Marcus, Dong, Huiping, Antila, Salli, Song, Eric, Alitalo, Kari, Thomas, Jean-Leon, Mao, Tianyang, Boisserand, Ligia Simoes Braga, Iwasaki, Akiko

2020

Overview

Immune surveillance against pathogens and tumours in the central nervous system is thought to be limited owing to the lack of lymphatic drainage. However, the characterization of the meningeal lymphatic network has shed light on previously unappreciated ways that an immune response can be elicited to antigens that are expressed in the brain . Despite progress in our understanding of the development and structure of the meningeal lymphatic system, the contribution of this network in evoking a protective antigen-specific immune response in the brain remains unclear. Here, using a mouse model of glioblastoma, we show that the meningeal lymphatic vasculature can be manipulated to mount better immune responses against brain tumours. The immunity that is mediated by CD8 T cells to the glioblastoma antigen is very limited when the tumour is confined to the central nervous system, resulting in uncontrolled tumour growth. However, ectopic expression of vascular endothelial growth factor C (VEGF-C) promotes enhanced priming of CD8 T cells in the draining deep cervical lymph nodes, migration of CD8 T cells into the tumour, rapid clearance of the glioblastoma and a long-lasting antitumour memory response. Furthermore, transfection of an mRNA construct that expresses VEGF-C works synergistically with checkpoint blockade therapy to eradicate existing glioblastoma. These results reveal the capacity of VEGF-C to promote immune surveillance of tumours, and suggest a new therapeutic approach to treat brain tumours.

• Publisher: Nature Publishing Group
• Subject: Animals / Antigens / Brain / Brain cancer / Brain Neoplasms - drug therapy / Brain Neoplasms - immunology / Brain Neoplasms - pathology / Brain tumors / CD8 antigen / CD8-Positive T-Lymphocytes - cytology / CD8-Positive T-Lymphocytes - immunology / Cell Cycle Checkpoints - drug effects / Cell Cycle Checkpoints - immunology / Cell Line, Tumor / Cell migration / Cell Movement / Central nervous system / Central Nervous System - immunology / Central Nervous System - pathology / Cross-Priming / Ectopic expression / Female / Glioblastoma / Glioblastoma - drug therapy / Glioblastoma - immunology / Glioblastoma - pathology / Growth factors / Health aspects / HEK293 Cells / Human health and pathology / Humans / Immune checkpoint / Immune clearance / Immune recognition / Immune response / Immune system / Immunologic Memory - immunology / Immunologic Surveillance - immunology / Immunosurveillance / Life Sciences / Lymph nodes / Lymph Nodes - immunology / Lymphangiogenesis / Lymphatic system / Lymphatic Vessels - immunology / Lymphocytes / Lymphocytes T / Male / Medical prognosis / Melanoma - drug therapy / Melanoma - immunology / Meninges - immunology / Mice / Mice, Inbred C57BL / mRNA / Nervous system / Observations / Physiological aspects / Priming / Programmed Cell Death 1 Receptor - antagonists & inhibitors / Programmed Cell Death 1 Receptor - immunology / Protective antigen / Surveillance / Transfection / Tumors / Vascular endothelial growth factor / Vascular endothelial growth factor C / Vascular Endothelial Growth Factor C - administration & dosage / Vascular Endothelial Growth Factor C - genetics / Vascular Endothelial Growth Factor C - metabolism / Vascular Endothelial Growth Factor C - therapeutic use