Abstract
BackgroundObesity 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.MethodsMonosodium 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.ResultsIn 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.ConclusionsTNF-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.
Highlights
Obesity confers increased risk for various types of cancer
Body weights, waist circumference and Lee’s index were all significantly increased in monosodium glutamate-induced obese (MSG-IO) mice (Fig. 1a–d) and diet-induced obese (DIO) mice (Fig. 1e–h). 105 H22 hepatoma cells within 0.2 ml of 0.9% saline were injected into control and MSG-IO mice. 17 days later, mice were sacrificed and tumor tissues were carefully dissected
Tumor PD‐L1 expression is increased in obese mice programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway is a key regulator in tumor immune evasion
Summary
Obesity confers increased risk for various types of cancer. 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. Overweight and obesity are associated with increased risk of liver cancer and malignant melanoma [2, 3]. The obesity-induced inflammatory microenvironment is a major drive of tumor progression, characterized by the presence of proinflammatory cytokines such as TNF-α [13, 14]. IL-6 is an important signaling molecule to affect immune system, lipid metabolism, insulin resistance, mitochondrial activity [15,16,17], and promotes hepatocellular carcinoma (HCC) and melanoma progression [18, 19]. TNF-α and IL-6 have been found as regulators of PD-L1 in a variety of cells [20, 21], whether they can regulate PD-L1 expression in HCC or melanoma is unknown
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