Canagliflozin primes antitumor immunity by triggering PD-L1 degradation in endocytic recycling
Ling Ding, Xi Chen, Wenxin Zhang, Xiaoyang Dai, Hongjie Guo, Xiaohui Pan, Yanjun Xu, Jianguo Feng, Meng Yuan, Xiaomeng Gao, Jian Wang, Xiaqing Xu, Sicheng Li, Honghai Wu, Ji Cao, Qiaojun He, Bo Yang
Ling Ding, Xi Chen, Wenxin Zhang, Xiaoyang Dai, Hongjie Guo, Xiaohui Pan, Yanjun Xu, Jianguo Feng, Meng Yuan, Xiaomeng Gao, Jian Wang, Xiaqing Xu, Sicheng Li, Honghai Wu, Ji Cao, Qiaojun He, Bo Yang
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Research Article Immunology

Canagliflozin primes antitumor immunity by triggering PD-L1 degradation in endocytic recycling

Abstract

Understanding the regulatory mechanisms of PD-L1 expression in tumors provides key clues for improving immune checkpoint blockade efficacy or developing novel oncoimmunotherapy. Here, we showed that the FDA-approved sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin dramatically suppressed PD-L1 expression and enhanced T cell–mediated cytotoxicity. Mechanistic study revealed that SGLT2 colocalized with PD-L1 at the plasma membrane and recycling endosomes and thereby prevented PD-L1 from proteasome-mediated degradation. Canagliflozin disturbed the physical interaction between SGLT2 and PD-L1 and subsequently allowed the recognition of PD-L1 by Cullin3SPOP E3 ligase, which triggered the ubiquitination and proteasome-mediated degradation of PD-L1. In mouse models and humanized immune-transformation models, either canagliflozin treatment or SGLT2 silencing significantly reduced PD-L1 expression and limited tumor progression — to a level equal to the PD-1 mAb — which was correlated with an increase in the activity of antitumor cytotoxic T cells. Notably, prolonged progression-free survival and overall survival curves were observed in the group of PD-1 mAb–treated patients with non–small cell lung cancer with high expression of SGLT2. Therefore, our study identifies a regulator of cell surface PD-L1, provides a ready-to-use small-molecule drug for PD-L1 degradation, and highlights a potential therapeutic target to overcome immune evasion by tumor cells.

Authors

Ling Ding, Xi Chen, Wenxin Zhang, Xiaoyang Dai, Hongjie Guo, Xiaohui Pan, Yanjun Xu, Jianguo Feng, Meng Yuan, Xiaomeng Gao, Jian Wang, Xiaqing Xu, Sicheng Li, Honghai Wu, Ji Cao, Qiaojun He, Bo Yang

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Figure 8

SGLT2 positively correlated with PD-L1 expression in lung cancer tissues.

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SGLT2 positively correlated with PD-L1 expression in lung cancer tissues...
(A and B) Patient tissues were stained with SGLT2 and PD-L1. Representative images of IHC staining of SGLT2 and PD-L1 in human lung cancer tissues (n = 100) were shown. Scale bar: 2 mm. The correlation analysis between SGLT2 and PD-L1 was performed, and the P value was calculated by the Pearson correlation test (P < 0.0001, r = 0.70136). –, negative expression; +, low expression; ++, medium expression; +++, high positive expression. (C and D) Kaplan-Meier survival curves of NSCLC patients’ PFS or OS. The low expression category includes those whose positive staining rate is smaller than 50%, whereas the high expression category greater than 50%. The Gehan-Breslow-Wilcoxon test was used to test for the difference between survival curves. (E) Tumor diameter based on the CT imaging was annotated with a red line. Scale bar: 10 cm. (F and G) Kaplan-Meier survival curves of NSCLC patients’ PFS or OS. The Gehan-Breslow-Wilcoxon test was used to test for the difference between survival curves. See also Supplemental Tables 3–5. (H) Diagram of the mechanism of SGLT2 regulating PD-L1.*P < 0.05, **P < 0.01; ***P < 0.001.