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Tumor extracellular vesicle-derived PD-L1 promotes T cell senescence through lipid metabolism reprogramming
Feiya Ma1,2, Xia Liu3, Yuanqin Zhang3
1Division of Infectious Diseases, Allergy & Immunology and Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA.
Abstract:
The limited success of cancer immunotherapy has posed challenges in treating patients with cancer. However, promising strides could be made with a deeper understanding of the factors that cause T cell dysfunction within the tumor microenvironment and by developing effective strategies to counteract tumor-induced immune suppression. Here, we report that tumor-derived extracellular vesicles (tEVs) can induce senescence and suppression in T cells. Programmed death ligand 1 (PD-L1), a key component within tEVs, induced DNA damage and hyperactive lipid metabolism in both human and mouse T cells. This caused an elevated expression of lipid metabolic enzymes and an increase in cholesterol and lipid droplet formation, leading to cellular senescence. At a molecular level, PD-L1 derived from tEVs activated the cAMP-response element binding protein (CREB) and signal transducer and activator of transcription (STAT) signaling, which promoted lipid metabolism and facilitated senescence in human and mouse T cells. Inhibiting EV synthesis in tumors or blocking CREB signaling, cholesterol synthesis, and lipid droplet formation in effector T cells averted the tEV-mediated T cell senescence in vitro and in vivo in cell adoptive transfer and melanoma mouse models. The same treatments also bolstered the antitumor efficacy of adoptive transfer T cell therapy and anti-PD-L1 checkpoint immunotherapy in both human and mouse melanoma models. These studies identified mechanistic links between tumor-mediated immune suppression and potential immunotherapy resistance, and they provide new strategies for cancer immunotherapy.
Insights
Tumor extracellular vesicles (tEVs) containing PD-L1 cause T cell dysfunction and senescence. Inhibiting tEVs or targeting lipid metabolism and CREB signaling enhances cancer immunotherapy effectiveness.
Area of Science:
- Immunology
- Cancer Biology
- Cellular Metabolism
Background:
- Cancer immunotherapy faces challenges due to T cell dysfunction within the tumor microenvironment.
- Tumor-induced immune suppression limits the efficacy of current cancer treatments.
Purpose of the Study:
- To investigate the role of tumor-derived extracellular vesicles (tEVs) in T cell dysfunction and senescence.
- To identify molecular mechanisms by which tEVs suppress T cell function.
- To explore novel therapeutic strategies to overcome tEV-mediated immune suppression in cancer immunotherapy.
Main Methods:
- Analysis of T cells exposed to tumor-derived extracellular vesicles (tEVs) in vitro and in vivo.
- Investigated the role of Programmed death ligand 1 (PD-L1) within tEVs.
- Assessed the impact of tEVs on T cell DNA damage, lipid metabolism, and senescence.
- Utilized molecular signaling pathway analysis (CREB, STAT).
- Employed genetic and pharmacological inhibition of EV synthesis, CREB signaling, and lipid metabolism.
- Evaluated therapeutic efficacy in adoptive transfer and melanoma mouse models.
Main Results:
- Tumor-derived extracellular vesicles (tEVs) induce T cell senescence and suppression.
- PD-L1 on tEVs causes DNA damage and hyperactive lipid metabolism (cholesterol, lipid droplets) in T cells.
- PD-L1 activates CREB and STAT signaling pathways, promoting T cell senescence.
- Inhibiting tEV synthesis or targeting CREB/cholesterol synthesis/lipid droplets reverses T cell senescence.
- Combined treatments enhance antitumor efficacy of T cell therapy and anti-PD-L1 immunotherapy.
Conclusions:
- tEVs, particularly PD-L1, are key mediators of T cell dysfunction and immune suppression in the tumor microenvironment.
- Targeting tEVs and associated signaling pathways (CREB, lipid metabolism) offers a promising strategy to enhance cancer immunotherapy.
- These findings provide mechanistic insights into immunotherapy resistance and suggest novel therapeutic approaches for cancer treatment.
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