4.7 Article

AMPK promotes antitumor immunity by downregulating PD-1 in regulatory T cells via the HMGCR/p38 signaling pathway

期刊

MOLECULAR CANCER
卷 20, 期 1, 页码 -

出版社

BMC
DOI: 10.1186/s12943-021-01420-9

关键词

Tregs; Tumor; PD-1; AMPK; HMGCR; Compound C; AICAR

资金

  1. Bio & Medical Technology Development Program of the National Research Foundation (NRF) - Korean government (MSIT) [NRF-2019R1A2C1006387, NRF2017M3A9C8060387, NRF-2020R1A5A8019180]

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In this study, it was found that AMP-activated protein kinase (AMPK) plays a regulatory role in the expression of PD-1 through the HMGCR/p38 MAPK/GSK3 beta signaling pathway in regulatory T cells (Tregs). This suggests that AMPK activators may have synergistic antitumor effects in murine tumor models when combined with other treatments.
Background AMP-activated protein kinase (AMPK) is a metabolic sensor that maintains energy homeostasis. AMPK functions as a tumor suppressor in different cancers; however, its role in regulating antitumor immunity, particularly the function of regulatory T cells (Tregs), is poorly defined. Methods AMPK alpha 1(fl/fl)Foxp3(YFP-Cre), Foxp3(YFP-Cre), Rag1(-/-), and C57BL/6 J mice were used for our research. Flow cytometry and cell sorting, western blotting, immuno-precipitation, immuno-fluorescence, glycolysis assay, and qRT-PCR were used to investigate the role of AMPK in suppressing programmed cell death 1 (PD-1) expression and for mechanistic investigation. Results The deletion of the AMPK alpha 1 subunit in Tregs accelerates tumor growth by increasing the expression of PD-1. Metabolically, loss of AMPK in Tregs promotes glycolysis and the expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a key enzyme of the mevalonate pathway. Mechanistically, AMPK activates the p38 mitogen-activated protein kinase (MAPK) that phosphorylates glycogen synthase kinase-3 beta (GSK-3 beta), inhibiting the expression of PD-1 in Tregs. Conclusion Our study identified an AMPK regulatory mechanism of PD-1 expression via the HMGCR/p38 MAPK/GSK3 beta signaling pathway. We propose that the AMPK activator can display synergic antitumor effect in murine tumor models, supporting their potential clinical use when combined with anti-PD-1 antibody, anti-CTLA-4 antibody, or a HMGCR inhibitor.

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