Inflammatory endothelial cells promote infiltration of antigen-licensed cytotoxic T cells in malignant gliomas after irradiation

Abstract

Insufficient T cell infiltration into malignant gliomas fundamentally limits the efficacy of adoptive T cell therapy. Here we show that fractionated irradiation overcomes this barrier by reprogramming the tumor endothelium towards an immune-recruiting interface. Using complementary murine glioma models combined with adoptive T cell transfer, antigen-specific vaccination, and single-cell transcriptomic and T cell receptor profiling, we demonstrate that irradiation enhances the accumulation, clonal expansion, and effector differentiation of tumor-specific CD8+ T cells. Irradiated tumors showed increased T cell receptor clonality and local enrichment of proliferative effector CD8 T cells with enhanced cytotoxic, interferon-responsive, and oxidative metabolic programs. Mechanistically, irradiation triggers a conserved interferon-driven endothelial program marked by antigen presentation and upregulation of adhesion molecules, including ICAM-1 and VCAM-1. This radiation-induced endothelial activation program preferentially seen in inflammatory endothelial subsets was conserved in human glioblastoma and linked to T cell recruitment and maintenance of activated CD8 T cell states. Functionally, irradiation synergized with adoptive T cell transfer and antigen-specific vaccination to promote glioma-specific T cell accumulation and effector differentiation, improving tumor control and survival. Together, these findings identify radiation-induced endothelial activation as a key regulator of T cell trafficking across the brain tumor vasculature highlighting the vascular niche as a critical determinant of immunotherapy efficacy and a rational target for combination strategies in glioblastoma.