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Canagliflozin primes antitumor immunity by triggering PD-L1 degradation in endocytic recycling
Ling Ding, … , Qiaojun He, Bo Yang
Ling Ding, … , Qiaojun He, Bo Yang
Published January 3, 2023
Citation Information: J Clin Invest. 2023;133(1):e154754. https://doi.org/10.1172/JCI154754.
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Research Article Immunology Article has an altmetric score of 54

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

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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 1

Canagliflozin suppresses PD-L1 expression in vitro and in vivo.

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Canagliflozin suppresses PD-L1 expression in vitro and in vivo.
(A) The ...
(A) The effect of various small-molecule drugs on PD-L1 expression. H292 cells were treated with a compound library containing 98 small-molecule drugs (approved by the FDA) for 24 hours, followed by Western blot analysis with PD-L1 antibody and quantification using ImageJ grayscale analysis. JQ1 was used as a positive control that significantly downregulated PD-L1 expression. (B and C) Western blots depicting the effect of canagliflozin and JQ1 on regulating different checkpoint protein expression, blots were run in parallel. (D and E) Western blots depicting canagliflozin-downregulated expression of PD-L1 under basal (D) and inducible conditions (E). NSCLC cell lines H292, H460, H1299, H358, H1944 and H1437 were treated with canagliflozin (20 μM) alone or together with IFN-γ (10 ng/mL) for 24 hours, followed by detection of PD-L1 protein level by Western blotting. (F and G) Canagliflozin downregulated the expression of PD-L1 on the cell surface. Cell surface PD-L1 levels were investigated by flow cytometry in H292 (F) and H1299 (G) cells. Data were presented as the mean ± SD of triplicate (H292) or quadruplicate (H1299) experiments. IgG, Isotype control antibody control. (H and I) 7 cases of patient–derived primary NSCLC cancer cells were subjected to Western blotting analysis for PD-L1 expression after treatment with canagliflozin (20 μM) alone or together with IFN-γ (10 ng/mL) for 24 hours. (J and K) H292-implanted NSG mouse model was treated daily with canagliflozin (50 mg/kg body weight, intragastric administration) or vehicle for 1 week. Protein lysates from tumors were analyzed via Western blot and quantified using Image J grayscale analysis. n = 6 mice per experimental group. Blue circles, vehicle group; purple squares, canagliflozin group. Data were analyzed via unpaired 2-tailed Students’ t test. *P < 0.05; **P < 0.01; ***P < 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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