Vascular leakage in non-small cell lung cancer is associated with immune evasion and poor response to immunotherapy

Leaky blood vessels are a hallmark of solid tumors. However, the molecular mechanisms and clinical implications of vascular leakage in human cancer remain unexplored. Here, we identified fibrinopeptide-A (FpA) as a robust in-situ marker of vascular leakage, analyzing diagnostic specimens from two non-small cell lung cancer (NSCLC) cohorts (N = 327 and N = 200). Mechanistically, FpA+ staining localized to discrete stromal niches characterized by increased endothelial VEGF receptor-2 phosphorylation, elevated VEGFA production by tumor cells and loss of the endothelial tyrosine phosphatase PTPRB. Immune profiling revealed reduced density of mature dendritic cells and granzyme B-expressing cytotoxic T cells in tumors with high-leakage. This leakage-associated immunosuppression was linked to the presence of tertiary lymphoid structures (TLS) in lung adenocarcinoma (LUAD). However, compared to low-leakage, TLS in high-leakage tumors were enriched in regulatory T cells and conferred no survival advantage. Patients with high vascular leakage exhibited a reduced overall survival. Moreover, in a separate immunotherapy cohort (N = 64), high-leakage was associated with poor response to anti-PD-1/PD-L1 treatment. This study establishes vascular leakage as an important prognostic factor in NSCLC, and provides mechanistic understanding and a methodological framework to stratify NSCLC patients with regard to responsiveness to immunotherapy.