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Autophagy inhibition enhances PD-L1 expression in gastric cancer

Article scientifique 2019 Anglais

Résumé

BACKGROUND: Autophagy, a process for degrading intracellular substances to maintain basal metabolic turnover, is known to be perturbed in gastric cancer. Programmed cell death-1 (PD-1) with its ligand (PD-L1) are important immune checkpoint proteins and their regulation by autophagy has been reported in mouse melanoma and human ovarian cancer. Here, we explored the interplay between autophagy and the PD1/PD-L1 axis in gastric cancer. METHODS: The expression of PD-L1 in gastric cancer cells was detected by Western blot and flow cytometry analysis. The effect of autophagy inhibition on PD-L1 expression was examined in vitro and in vivo. The molecular mechanisms of the regulation of PD-L1 by autophagy were evaluated in gastric cancer cell lines. The clinical relevance of autophagy-related markers p62/SQSTM1 and LC3 with PD-L1 was evaluated in 137 patients with gastric cancer. RESULTS: We found that inhibition of autophagy by pharmacological inhibitors or small interfering RNAs increased the levels of PD-L1 in cultured gastric cancer cells and in xenografts. Interferon (IFN)-γ also promoted PD-L1 gene transcription, whose action was enhanced by autophagy inhibition. Mechanistically, autophagy inhibition led to the accumulation of p62/SQSTM1 and activation of nuclear factor (NF)-κB, in which NF-κB inhibition or p62/SQSTM1 knockdown attenuated PD-L1 induction by autophagy inhibition. Immunohistochemical staining of primary tumor tissues of 137 patients with gastric cancer showed that LC3 and p62/SQSTM1 protein levels were positively correlated with PD-L1 (LC3, p < 0.001; p62/SQSTM1, p < 0.05). The expression of PD-L1 was also positively correlated with tumor lymphocyte infiltration (p < 0.001). CONCLUSIONS: We discovered that autophagy regulates PD-L1 expression in gastric cancer through the p62/SQSTM1-NF-κB pathway. Pharmacological modulation of autophagy may thus influence the therapeutic efficacy of PD-L1 blockade in gastric cancer.

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Wang, X., Wu, W., Gao, J., Li, Z., Dong, B., Lin, X., Li, Y., Li, Y., Gong, J., Qi, C., Peng, Z., Yu, J., Shen, L. (2019). Autophagy inhibition enhances PD-L1 expression in gastric cancer. https://doi.org/10.1186/s13046-019-1148-5

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Auteur(s)

Xiaojuan Wang William Ka Kei Wu Jing Gao Zhongwu Li Bin Dong Xiaoting Lin Yilin Li Yanyan Li Jifang Gong Changsong Qi Zhi Peng Jun Yu Lin Shen

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