Li Zhi, Zhang Cai, Du Jing-Xia, Zhao Jia, Shi Meng-Ting, Jin Man-Wen, Liu Hui
1Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China.
Cancer Cell Int. 2020 May 20;20:179. doi: 10.1186/s12935-020-01269-w. eCollection 2020.
Obesity confers increased risk for various types of cancer. PD-L1 is a key molecule in tumor immune evasion by inducing T cell exhaustion. The relationship between obesity and PD-L1 is still ambiguous. This study was designed to reveal the development of hepatocellular carcinoma and melanoma in obese mice and to investigate if adipocytes regulate PD-L1 expression and the underlying mechanism.
Monosodium glutamate-induced obese mice were inoculated with H22 tumor cells and High fat diet (HFD)-induced obese mice were inoculated with B16-F1 mouse melanoma cells. Human hepatoma HepG2 cells and B16-F1 cells were treated with conditional media from 3T3-L1 adipocytes (adi-CM). Neutralized anti-TNF-α and anti-IL-6 antibodies and inhibitor of NF-κB or STAT3 were used to reveal the mechanism of effect of adi-CM.
In obese mice, H22 and B16-F1 tumor tissues grew faster and PD-L1 expression in tumor tissue was increased. Adi-CM up-regulated PD-L1 level in HepG2 and B16-F1 cells in vitro. Differentiated 3T3-L1 adipocytes secreted TNF-α and IL-6, and neutralizing TNF-α and/or IL-6 reduced PD-L1 expression in adi-CM-treated cells. p-NF-κB/NF-κB level was downregulated in HepG2 and B16-F1 cells, and p-STAT3/STAT3 level was also decreased in HepG2 cells. In addition, inhibitor of NF-κB or STAT3 reversed the effect of adi-CM on PD-L1 expression.
TNF-α and IL-6 secreted by adipocytes up-regulates PD-L1 in hepatoma and B16-F1 cells, which may be at least partially involved in the role of obesity in promoting tumor progression.
肥胖会增加患各种癌症的风险。程序性死亡受体配体1（PD-L1）是通过诱导T细胞耗竭实现肿瘤免疫逃逸的关键分子。肥胖与PD-L1之间的关系仍不明确。本研究旨在揭示肥胖小鼠肝细胞癌和黑色素瘤的发展情况，并研究脂肪细胞是否调节PD-L1表达及其潜在机制。
用谷氨酸钠诱导肥胖小鼠接种H22肿瘤细胞，用高脂饮食（HFD）诱导肥胖小鼠接种B16-F1小鼠黑色素瘤细胞。用人肝癌HepG2细胞和B16-F1细胞分别用3T3-L1脂肪细胞的条件培养基（adi-CM）处理。使用中和抗TNF-α和抗IL-6抗体以及NF-κB或STAT3抑制剂来揭示adi-CM的作用机制。
在肥胖小鼠中，H22和B16-F1肿瘤组织生长更快，肿瘤组织中PD-L1表达增加。adi-CM在体外上调了HepG2和B16-F1细胞中的PD-L1水平。分化的3T3-L1脂肪细胞分泌TNF-α和IL-6，中和TNF-α和/或IL-6可降低adi-CM处理细胞中的PD-L1表达。HepG2和B16-F1细胞中p-NF-κB/NF-κB水平下调，HepG2细胞中p-STAT3/STAT3水平也降低。此外，NF-κB或STAT3抑制剂可逆转adi-CM对PD-L1表达的影响。
脂肪细胞分泌的TNF-α和IL-6上调肝癌细胞和B16-F1细胞中的PD-L1，这可能至少部分参与了肥胖促进肿瘤进展的作用。
