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- W4366184253 abstract "Acetyl-CoA is a key metabolic intermediate with an indispensable role in sustaining tumor cell growth as well as in regulating genes transcription. However, its role in immune checkpoint regulation and tumor immune evasion remains unclear. Herein, we demonstrate that ACLY, the enzyme controlling cytosolic acetyl-CoA biogenesis, drives CD8+T cells mediated tumor immune evasion through upregulating endogenous and IFN-r induced PD-L1 expression. We first used integrative analysis to explore the association of acetyl-CoA metabolic pathway and ACLY with immune features across multiple cancer types. We further investigated the efficacy of ACLY inhibitor, SB204990 or combinatory treatment of SB204990 and anti-PD-1 antibody in mouse models. In vitroassays were carried out to examine the regulating roles of ACLY on PD-L1. In addition, multiple interventions of AcCoA metabolism pathways including siRNA and small molecular inhibitors were employed to assess the role of cytosolic acetyl-CoA in regulating PD-L1 expression. Lastly, ChIP assays was performed to examine the mechanism of AcCoA and ACLY regulated PD-L1 expression. Our bioinformatics analysis revealed a strong association between acetyl-CoA metabolic pathway and immune features. We further demonstrated that blockade of ACLY significantly reduced tumor burden by promoting anti-tumor immunity. In addition, knockdown of ACLY rendered tumors more sensitive to anti-PD-1 treatment. Importantly, perturbing cytosolic acetyl-CoA level by knockdown of ACSS2 and PDC inhibitor caused down-and up-regulated PD-L1 levels, respectively, while MPC inhibitor treatment had no effect on PD-L1 expression. Mechanistically, ACLY maintains cytosolic acetyl-CoA level, which promoted histone acetylation at the promoter of CD274 mediated by P300, leading to downstream PD-L1 expression on tumors. Collectively, these data delineate an acetyl-CoA metabolism dependent epigenetic mechanism contributing to tumor immune evasion, and the combination of ACLY inhibitor and anti-PD-1 antibody provides potential therapeutic strategies for melanoma treatment." @default.
- W4366184253 created "2023-04-19" @default.
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- W4366184253 date "2023-05-01" @default.
- W4366184253 modified "2023-09-28" @default.
- W4366184253 title "1220 Cytosolic acetyl-CoA drives tumor immune evasion via the epigenetic regulation of PD-L1 in melanoma" @default.
- W4366184253 doi "https://doi.org/10.1016/j.jid.2023.03.1234" @default.
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