Endothelial OX40 activation facilitates tumor cell escape from T cell surveillance through S1P/YAP-mediated angiogenesis
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
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
View: Text | PDF
Research Article Immunology Oncology

Endothelial OX40 activation facilitates tumor cell escape from T cell surveillance through S1P/YAP-mediated angiogenesis

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

×

Figure 4

Serum EGF serves as a biomarker for predicting the efficacy of OX40 agonists.

Options: View larger image (or click on image) Download as PowerPoint
Serum EGF serves as a biomarker for predicting the efficacy of OX40 agon...
(A) EGF levels were measured in sera from patients with CRC and healthy control participants (HC) (n = 48). (B and C) The CRC patients were divided into 2 groups based on the median value of serum EGF levels: the EGF-low group and the EGF-high group. (B) Representative images of multicolor immunofluorescence using anti-OX40 (orange), anti-CD31 (white), anti-CD3 (red), and anti-Ki67 (green) antibodies in tumor tissues of CRC patients with high or low serum EGF levels (n = 5). Scale bars: 50 μm. (C) Statistical analysis of OX40+ EC percentages in tumor tissues of indicated CRC patients (n = 5). (D) Tumor inhibition values of anti-human αOX40 treatment (20 μg/mouse, i.p.) for PDX tumors derived from CRC patients with high or low serum EGF levels in BALB/c nude mice (n = 5). (E) Representative images of multicolor immunofluorescence using anti-CD3, anti-CD31, and anti-OX40 antibodies in PDX tumors from CRC patients with high or low serum EGF levels (n = 5). Scale bars: 50 μm. (F and G) Statistical analysis of Ki67+ T cell percentages (F) and vascular density (G; n = 5). (H) Tumor inhibition values of anti-human αOX40 (20 μg/mouse, i.p.), gefitinib (80 mg/kg, oral gavage), or their combination for PDX tumors from CRC patients with high serum EGF levels (n = 5). One-way ANOVA (A, C, D, F, and G) or 2-tailed Student’s t test (H) was used for statistical analysis.