Endothelial OX40 activation facilitates tumor cell escape from T cell surveillance through S1P/YAP-mediated angiogenesis
Baoyu He, … , Qingli Bie, Bin Zhang
Baoyu He, … , Qingli Bie, Bin Zhang
Published March 3, 2025
Citation Information: J Clin Invest. 2025;135(5):e186291. https://doi.org/10.1172/JCI186291.
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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

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Figure 1

OX40 activation promotes tumor growth and metastasis in T cell–immunocompromised mice.

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OX40 activation promotes tumor growth and metastasis in T cell–immunocom...
(A and B) Images (left) and volume (right) of subcutaneous tumors established using MC38 cells treated with mouse OX40L protein (OX40L; 200 mg/mouse, i.p.) or anti–mouse OX40 agonistic antibody (αOX40; 100 μg/mouse, i.p.) in BALB/c nude mice (A) and NSG mice (B) (n = 8). (C–E) Bioluminescent intensity (C), metastatic nodules in the liver (D), and survival of mice (E) from the colon orthotopic metastasis model established using MC38 cells treated with mouse OX40L protein (OX40L; 200 mg/mouse, i.p.) or anti–mouse OX40 agonistic antibody (αOX40; 100 μg/mouse, i.p.) in NSG mice (n = 6). (F–H) Bioluminescent intensity (F), metastatic nodules in the lung (G), and survival of mice (H) from the pulmonary metastasis model established using MC38 cells treated with mouse OX40L protein (OX40L; 200 mg/mouse, i.p.) or anti–mouse OX40 agonistic antibody (αOX40; 100 μg/mouse, i.p.) in NSG mice (n = 6). (I) Anti–mouse CD3 antibody (200 μg/mouse, i.p.) was applied to deplete T cells in C57BL/6J mice. Then, CD3+ T cells were measured by flow cytometric analysis in CD45+ single-cell suspensions sorted from subcutaneous tumors in CD3+ T cell–depleted mice and IgG control mice (n = 3). (J) Images (left) and volume (right) of subcutaneous tumors established using MC38 cells treated with vehicle or anti–mouse OX40 agonistic antibody (αOX40; 100 μg/mouse, i.p.) in IgG mice and CD3+ T cell–depleted mice (n = 8). Two-way ANOVA (A, B, and J), 1-way ANOVA (C, D, F, G, and I), or log-rank test (E and H) was used for statistical analysis. Lg ROI, log10 region of interest.