Endothelial OX40 activation facilitates tumor cell escape from T cell surveillance through S1P/YAP-mediated angiogenesis
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
- Guanjun Dong (ORCID: https://orcid.org/0000-0002-5444-2416)
- Huabao Xiong (ORCID: https://orcid.org/0000-0003-0180-2104)
- Lunhua Huang
- Hongli Pan (ORCID: https://orcid.org/0000-0001-9205-1232)
- Jilan Liu
- Qingli Bie
- Rou Zhao
- Baoyu He (ORCID: https://orcid.org/0000-0002-5476-8651)
- Yingying Wei (ORCID: https://orcid.org/0000-0003-2177-2301)
- Xiao Zhang (ORCID: https://orcid.org/0000-0001-9105-7528)
- Sen Wang (ORCID: https://orcid.org/0000-0001-6358-1672)
- Bin Zhang (ORCID: https://orcid.org/0000-0003-1323-8678)
- Junfeng Zhang (ORCID: https://orcid.org/0000-0001-9810-661X)
- Xu Zhang (ORCID: https://orcid.org/0000-0002-3680-513X)
- Dongliang Yang (ORCID: https://orcid.org/0000-0002-8605-6720)
- Yanhua Zhang (ORCID: https://orcid.org/0000-0003-0732-5038)
- Jing Liang (ORCID: https://orcid.org/0000-0002-4042-1497)
- Ming‐Yi Wang (ORCID: https://orcid.org/0000-0002-7710-4743)
- Fengyun Dong
- Zhang Bao-gui (ORCID: https://orcid.org/0000-0003-3169-0676)
- Mingsheng Zhao
Institutions
- Jiangsu University (CN)
- Shanghai Jiao Tong University (CN)
- Renji Hospital (CN)
- Fudan University Shanghai Cancer Center (CN)
- Jining Medical University (CN)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-03-02
- DOI
- https://doi.org/10.1172/jci186291
- Citations
- 8
- Primary Topic
- Hippo pathway signaling and YAP/TAZ
- Type
- article
- Field-Weighted Citation Impact
- 9.21
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Natural Science Foundation of Shandong Province