Lipogenesis governs PD-L1-dependent immune escape to promote melanoma growth
Journal of Investigative Dermatology(2019)
Abstract
Abnormal cellular metabolism and dysregulated anti-tumor immunity both greatly contributes to tumor progression. However, the crosstalk between these two crucial pathogenic characteristics has not been investigated. Herein, we report that enhanced lipogenesis, the hallmark of cancer metabolism, promotes PD-L1 expression and tumor cell immune escape to facilitate melanoma cell proliferation. We first found that the knockdown of lipogenic enzymes, including ATP-citrate lyase (ACL), acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FASN), led to significant decrease of PD-L1 protein abundance and membrane PD-L1 expression in melanoma cell. In addition, the pharmacological inhibition of cholesterol synthetic enzyme HMG-CoA reductase by simvastatin prominently reduced PD-L1 expression as well. Further, we proved that gp100-specific CD8+ T cells co-cultured with melanoma cells of lipogenesis deficiency produced more perforin and granzymes B, resulting in more melanoma cell apoptosis and impaired cell proliferation. Importantly, this effect was partially reversed by anti-PD-1 antibody treatment or the overexpression of PD-L1 in melanoma cell. What's more, we showed that lipogenesis regulated PD-L1 expression in both transcription-dependent and transcription-independent manners. Altogether, our results demonstrated that lipogenesis governs PD-L1-dependent immune escape to promote melanoma growth. Targeting lipogenesis could be potent therapeutic approach for melanoma by simultaneously intervening cancer metabolism and anti-tumor immunity.
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Key words
melanoma growth,immune
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