Intravital Imaging Identifies the VEGF-TXA2 Axis as a Critical Promoter of PGE2 Secretion from Tumor Cells and Immune Evasion

Abstract

Prostaglandin E₂ (PGE₂) promotes tumor progression through evasion of antitumor immunity. In stark contrast to cyclooxygenase-dependent production of PGE₂, little is known whether PGE₂ secretion is regulated within tumor tissues. Here, we show that VEGF-dependent release of thromboxane A₂ (TXA₂) triggers Ca²⁺ transients in tumor cells, culminating in PGE₂ secretion and subsequent immune evasion in the early stages of tumorigenesis. Ca²⁺ transients caused cPLA2 activation and triggered the arachidonic acid cascade. Ca²⁺ transients were monitored as the surrogate marker of PGE₂ secretion. Intravital imaging of Braf^V600E mouse melanoma cells revealed that the proportion of cells exhibiting Ca²⁺ transients is markedly higher in vivo than in vitro. The TXA₂ receptor was indispensable for the Ca²⁺ transients in vivo, high intratumoral PGE₂ concentration, and evasion of antitumor immunity. Notably, treatment with a VEGF receptor antagonist and an anti-VEGF antibody rapidly suppressed Ca²⁺ transients and reduced TXA₂ and PGE₂ concentrations in tumor tissues. These results identify the VEGF-TXA₂ axis as a critical promoter of PGE₂-dependent tumor immune evasion, providing a molecular basis underlying the immunomodulatory effect of anti-VEGF therapies. SIGNIFICANCE: This study identifies the VEGF-TXA₂ axis as a potentially targetable regulator of PGE₂ secretion, which provides novel strategies for prevention and treatment of multiple types of malignancies.