Data from Intravital Imaging Identifies the VEGF–TXA<sub>2</sub> Axis as a Critical Promoter of PGE<sub>2</sub> Secretion from Tumor Cells and Immune Evasion

<div>Abstract<p>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 <i>in vivo</i> than <i>in vitro</i>. The TXA₂ receptor was indispensable for the Ca²⁺ transients <i>in vivo</i>, 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.</p>Significance:<p>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.</p></div>