Tailoring vascular phenotype through AAV therapy promotes anti-tumor immunity in glioma.

Abstract

Glioblastomas are aggressive brain tumors that are largely immunotherapy resistant. This is associated with immunosuppression and a dysfunctional tumor vasculature, which hinder Tcell infiltration. LIGHT/TNFSF14 can induce high endothelial venules (HEVs) and tertiary lymphoid structures (TLS), suggesting that its therapeutic expression could promote Tcell recruitment. Here, we use a brain endothelial cell-targeted adeno-associated viral (AAV) vector to express LIGHT in the glioma vasculature (AAV-LIGHT). We found that systemic AAV-LIGHT treatment induces tumor-associated HEVs and Tcell-rich TLS, prolonging survival inαPD-1-resistant murine glioma. AAV-LIGHT treatment reduces Tcell exhaustion and promotes TCF1+CD8+ stem-like Tcells, which reside in TLS and intratumoral antigen-presenting niches. Tumor regression upon AAV-LIGHT therapy correlates with tumor-specific cytotoxic/memory Tcell responses. Our work reveals that altering vascular phenotype through vessel-targeted expression of LIGHT promotes efficient anti-tumor Tcell responses and prolongs survival in glioma. These findings have broader implications for treatment of other immunotherapy-resistant cancers.