Tiarne van de Walle: Shining the LIGHT on Glioblastoma: Understanding and exploiting vascular and immune co-targeting

Abstract

Patients diagnosed with glioblastoma (GBM) have an extremely poor prognosis despite extensive research in the recent years, with a five-year overall survival of only 7%. There is a multitude of barriers to effective treatment in GBM, including low levels of T cell infiltration. Chronic inflammation in cancer can lead to the formation of ectopic clusters of lymphoid tissue known as tertiary lymphoid structures (TLS), as well as specialised blood vessels called tumour-associated high endothelial venules (TA-HEVs), which are involved in the extravasation of different immune cell subsets. Both TLS and TA-HEVs have been associated with increased immune cell infiltration and prolonged survival in numerous peripheral cancers. In this work, we aimed to improve the anti-glioma immune response by increasing the infiltration of T cells through induction of TLS and TA-HEVs. Further, we aimed to deeply explore the characteristics and roles of these two components in the GBM setting. 

In Paper I, we pre-screened a panel of lymphoneogenic cytokines and selected LIGHT as the most promising therapeutic candidate. We then targeted LIGHT to the brain endothelial cells of glioma-bearing mice utilising an adeno-associated viral (AAV) vector (AAV-LIGHT). We found that this approach resulted in prolonged survival in association with the formation of TLS and functional MAdCAM-1+ TA-HEVs, as well as the promotion of effector/memory T cell responses and the TCF1+CD8+ stem-like T cell population. 

In Paper II, we correlated the presence of TLS with improved survival in GBM patients. We then combined advanced spatial transcriptomics techniques with functional studies in murine glioma to establish the developmental timeline of TLS in GBM, including the critical role of CCR7+CD4+ T cells with LTi-like features. 

In Paper III, we employed a murine knockout model of MAdCAM-1 to demonstrate its necessity in the anti-glioma immune response through the promotion of TCF1+CD8+ stem-like T cells. Furthermore, we identified the presence of TA-HEVs in human GBM in association with infiltrating T cells.

Altogether, this work uncovers previously unknown mechanisms and highlights the potential of targeting the immune/vascular interface as a therapeutic option for GBM.