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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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 6

Canagliflozin effectively inhibits tumor growth in a PBMC humanized xenograft model.

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Canagliflozin effectively inhibits tumor growth in a PBMC humanized xeno...
(A) Scheme representing the experimental procedure. s.c, subcutaneous; qd, 1 a day; i.g., intragastric; IOCV, injection of caudal vein; biw, twice per week. (B) Tumor growth of H292 cells in PBMC humanized NSG mice treated with vehicle, canagliflozin, or anti-PD-1 Ab. n = 7 mice per group. (C) PD-L1 level in extracted tumor cells was evaluated by FACS. (D and E) Tumor-infiltrating CD45+CD3+ T cells and CD45+CD8+ T cells were detected by FACS. (F) Tumor growth of H292 cells in immuno-deficient NSG mice when treated with vehicle, canagliflozin, or anti-PD-1 Ab. n = 6 mice per group. (G) PD-L1 level in extracted tumor cells from immuno-deficient NSG mice was evaluated by FACS. (H and I) shSGLT2 significantly inhibited the tumor growth in the humanized NSG mouse model. H292 cells with or without SGLT2 knocked down were injected into PBMC humanized NSG mice and tumor growth was measured. n = 6 mice per group. (J) The surface level of PD-L1 on tumor cells were evaluated by FACS. (K and L) Tumor infiltrating CD45+CD3+ T cells and CD45+CD8+ T cells were detected by FACS. (M and N) CD45+CD3+ T cells and CD45+CD8+ T cells in blood were detected by FACS. Data represent mean ± SD. Statistical significance was determined by 1-way ANOVA with Dunnett’s post hoc test (B–E and G) and unpaired 2-tailed Students’ t test (H and J–N). *P < 0.05; **P < 0.01; ***P < 0.001.