Abstract
Understanding the complexity of the tumor microenvironment is vital for improving immunotherapy outcomes. Here, we report that the T cell costimulatory molecule OX40 was highly expressed in tumor endothelial cells (ECs) and was negatively associated with the prognosis of patients, which is irrelevant to T cell activation. Analysis of conditional OX40 loss- and gain-of-function transgenic mice showed that OX40 signal in ECs counteracted the antitumor effects produced in T cells by promoting angiogenesis. Mechanistically, leucine-rich repeat–containing GPCR5 (Lgr5+ ) cancer stem cells induced OX40 expression in tumor ECs via EGF/STAT3 signaling. Activated OX40 interacted with Spns lysolipid transporter 2 (Spns2), obstructing the export of sphingosine 1-phosphate (S1P) and resulting in S1P intracellular accumulation. Increased S1P directly bound to Yes 1–associated protein (YAP), disrupting its interaction with large tumor suppressor kinase 1 (LATS1) and promoting YAP nuclear translocation. Finally, the YAP inhibitor verteporfin enhanced the antitumor effects of the OX40 agonist. Together, these findings reveal an unexpected protumor role of OX40 in ECs, highlighting the effect of nonimmune cell compartments on immunotherapy.
Authors
Baoyu He, Rou Zhao, Baogui Zhang, Hongli Pan, Jilan Liu, Lunhua Huang, Yingying Wei, Dong Yang, Jing Liang, Mingyi Wang, Mingsheng Zhao, Sen Wang, Fengyun Dong, Junfeng Zhang, Yanhua Zhang, Xu Zhang, Xiao Zhang, Guanjun Dong, Huabao Xiong, Qingli Bie, Bin Zhang
Graphical abstract
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)