OX40 expressed in endothelial cells facilitates tumor cells to escape from T-cell surveillance through S1P-YAP axis

Activation of immune cells is currently one of the most promising approaches for the cancer treatment. However, clinical trials for T-cell activation therapy have not reached expected results without explicit reasons. In the present study, we report that the co-stimulatory molecule OX40 is highly expressed in endothelial cells (ECs) of tumor tissues. Clinically, high expression of OX40 in ECs is negatively associated with the prognosis of tumor patients, and this is irrelevant to T-cell activation or not. Analysis of conditional OX40 loss- and gain-of-function transgenic mice demonstrated that OX40 signals promote angiogenesis and facilitate the tumour development. Mechanistically, Lgr5+ cancer stem cells induced high OX40 expression in tumour ECs via EGF-STAT3 signal transduction. In ECs, activated OX40 interacted with Spns2, obstructing sphingosine-1-phosphate (S1P) export and resulting in its intracellular accumulation. S1P directly bound to YAP, disrupting its interaction with the LATS1 kinase and promoting YAP nuclear translocation. Finally, the YAP inhibitor Verteporfin enhanced the anti-tumour effects of the OX40 agonist. In addition, their combination exhibited greater efficacy than that of the OX40 agonist and anti-PD-1 antibody. Together, the findings revealed a unexpected pro-tumour functions of OX40 activation in ECs, highlighting the impact of non-immune cell compartment on immunotherapy and the complexity of tumour microenvironment.