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Inhibition of GFAT1 in lung cancer cells destabilizes PD-L1 protein
Wenshu Chen1, Bryanna Saxton1, Mathewos Tessema1
1Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, NM, USA.
Abstract:
Immunotherapy using checkpoint blockers (antibodies) has been a major advance in recent years in the management of various types of solid cancers including lung cancer. One target of checkpoint blockers is programmed death ligand 1 (PD-L1) expressed by cancer cells, which engages programmed death 1 on T cells and Natural Killer (NK) cells resulting in suppression of their activation and cancer-killing function, respectively. Apart from antibodies, other clinically relevant agents that can inhibit PD-L1 are limited. PD-L1 protein stability depends on its glycosylation. Here we show that l-glutamine:d-fructose-6-phosphate amidotransferase 1 (GFAT1), a rate-limiting enzyme of the hexosamine biosynthesis pathway, which produces uridine diphosphate-N-acetyl-β-glucosamine, a precursor for glycosylation, is required for the stability of PD-L1 protein. Inhibition of GFAT1 activity markedly reduced interferon gamma (IFNγ)-induced PD-L1 levels in various lung cancer cell lines. GFAT1 inhibition suppressed glycosylation of PD-L1 and accelerated its proteasomal degradation. Importantly, inhibition of GFAT1 in IFNγ-treated cancer cells enhanced the activation of T cells and the cancer-killing activity of NK cells. These findings support using GFAT1 inhibitors to manipulate PD-L1 protein level that could augment the efficacy of immunotherapy for lung cancer.
Insights
Inhibiting GFAT1 reduces PD-L1 stability, enhancing T cell and NK cell cancer-killing activity. This suggests GFAT1 inhibitors could improve immunotherapy for lung cancer.
Area of Science:
- Oncology
- Immunology
- Biochemistry
Background:
- Immunotherapy with checkpoint blockers has advanced cancer treatment, particularly for lung cancer.
- Programmed death ligand 1 (PD-L1) on cancer cells suppresses T cell and NK cell anti-cancer functions.
- Current agents inhibiting PD-L1 are limited, highlighting a need for novel strategies.
Purpose of the Study:
- To investigate the role of GFAT1 in PD-L1 protein stability and its potential as a therapeutic target.
- To explore the impact of GFAT1 inhibition on PD-L1 glycosylation and degradation.
- To evaluate the effect of GFAT1 inhibition on immune cell activation and anti-cancer activity.
Main Methods:
- Assessed the effect of GFAT1 inhibition on interferon gamma (IFNγ)-induced PD-L1 levels in lung cancer cell lines.
- Examined the impact of GFAT1 inhibition on PD-L1 glycosylation and proteasomal degradation.
- Measured T cell activation and NK cell cancer-killing activity in response to GFAT1 inhibition in IFNγ-treated cancer cells.
Main Results:
- GFAT1 is crucial for PD-L1 protein stability.
- Inhibition of GFAT1 reduced PD-L1 glycosylation and accelerated its degradation.
- GFAT1 inhibition enhanced T cell activation and NK cell-mediated cancer cell killing.
Conclusions:
- GFAT1 plays a key role in regulating PD-L1 protein levels.
- Targeting GFAT1 offers a novel strategy to enhance immunotherapy efficacy in lung cancer by modulating PD-L1.
- GFAT1 inhibitors may augment anti-cancer immune responses, improving outcomes for lung cancer patients.
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