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

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