Intravital Imaging Identifies the VEGF-TXA 2 Axis as a Critical Promoter of PGE 2 Secretion from Tumor Cells and Immune Evasion.

Prostaglandin E ₂ (PGE ₂ ) promotes tumor progression through evasion of antitumor immunity. In stark contrast to cyclooxygenase-dependent production of PGE ₂ , little is known whether PGE ₂ secretion is regulated within tumor tissues. Here, we show that VEGF-dependent release of thromboxane A ₂ (TXA ₂ ) triggers Ca ²⁺ transients in tumor cells, culminating in PGE ₂ secretion and subsequent immune evasion in the early stages of tumorigenesis. Ca ²⁺ transients caused cPLA2 activation and triggered the arachidonic acid cascade. Ca ²⁺ transients were monitored as the surrogate marker of PGE ₂ secretion. Intravital imaging of Braf ^V600E mouse melanoma cells revealed that the proportion of cells exhibiting Ca ²⁺ transients is markedly higher in vivo than in vitro . The TXA ₂ receptor was indispensable for the Ca ²⁺ transients in vivo , high intratumoral PGE ₂ concentration, and evasion of antitumor immunity. Notably, treatment with a VEGF receptor antagonist and an anti-VEGF antibody rapidly suppressed Ca ²⁺ transients and reduced TXA ₂ and PGE ₂ concentrations in tumor tissues. These results identify the VEGF-TXA ₂ axis as a critical promoter of PGE ₂ -dependent tumor immune evasion, providing a molecular basis underlying the immunomodulatory effect of anti-VEGF therapies. SIGNIFICANCE: This study identifies the VEGF-TXA ₂ axis as a potentially targetable regulator of PGE ₂ secretion, which provides novel strategies for prevention and treatment of multiple types of malignancies.
(©2021 American Association for Cancer Research.)