Tailoring vascular phenotype through AAV therapy promotes anti-tumor immunity in glioma
LIGHT; TNFSF14; antigen-presenting niches; glioblastoma; high endothelial venules; lymphotoxin αβ; stem-like T cells; tertiary lymphoid structures.- Cancer Cell
- 38.585
- 2023 Jun 12;41(6):1134-1151.e10.
- 单细胞测序
- 神经系统
- 胶质瘤
Abstract
Glioblastomas are aggressive brain tumors that are largely immunotherapy resistant. This is associated with immunosuppression and a dysfunctional tumor vasculature, which hinder T cell infiltration. LIGHT/TNFSF14 can induce high endothelial venules (HEVs) and tertiary lymphoid structures (TLS), suggesting that its therapeutic expression could promote T cell 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 T cell-rich TLS, prolonging survival in αPD-1-resistant murine glioma. AAV-LIGHT treatment reduces T cell exhaustion and promotes TCF1+CD8+ stem-like T cells, which reside in TLS and intratumoral antigen-presenting niches. Tumor regression upon AAV-LIGHT therapy correlates with tumor-specific cytotoxic/memory T cell responses. Our work reveals that altering vascular phenotype through vessel-targeted expression of LIGHT promotes efficient anti-tumor T cell responses and prolongs survival in glioma. These findings have broader implications for treatment of other immunotherapy-resistant cancers. Keywords: LIGHT; TNFSF14; antigen-presenting niches; glioblastoma; high endothelial venules; lymphotoxin αβ; stem-like T cells; tertiary lymphoid structures.
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