Autophagy inhibition enhances PD-L1 expression in gastric cancer.

Abstract

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.

• Authors: Xiaojuan Wang, William K K Wu, Jing Gao, Zhongwu Li, Bin Dong, Xiaoting Lin, Yilin Li, Yanyan Li, Jifang Gong, Changsong Qi, Zhi Peng, Jun Yu, Lin Shen
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 38 Issue 1 Pg. 140 (Mar 29 2019) ISSN: 1756-9966 [Electronic] England
• PMID: 30925913 (Publication Type: Journal Article)

Chemical References

• B7-H1 Antigen
• CD274 protein, human

Topics

• Animals
• Autophagy
• B7-H1 Antigen (metabolism)
• Cell Line, Tumor
• Down-Regulation
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Mice
• Mice, Nude
• Neoplasm Staging
• Neoplasm Transplantation
• Stomach Neoplasms (metabolism, pathology)