Related Experiment Video
Updated: Sep 27, 2025
In Vivo Immunogenicity Screening of Tumor-Derived Extracellular Vesicles by Flow Cytometry of Splenic T Cells
Published on: September 23, 2021
Targeting the liver X receptor with dendrogenin A differentiates tumour cells to secrete immunogenic exosome-enriched
Michel Record1, Mehdi Attia1, Kevin Carayon1
1Team "Cholesterol Metabolism and Therapeutic Innovations" Cancer Research Centre of Toulouse (CRCT), UMR 1037 INSERM, UMR 5071 CNRS, Université de Toulouse III, Equipe labellisée par la Ligue Nationale Contre le Cancer, French network for Nutrition And Cancer Research (NACRe network), France.
Abstract:
Tumour cells are characterized by having lost their differentiation state. They constitutively secrete small extracellular vesicles (sEV) called exosomes when they come from late endosomes. Dendrogenin A (DDA) is an endogenous tumour suppressor cholesterol-derived metabolite. It is a new class of ligand of the nuclear Liver X receptors (LXR) which regulate cholesterol homeostasis and immunity. We hypothesized that DDA, which induces tumour cell differentiation, inhibition of tumour growth and immune cell infiltration into tumours, could functionally modify sEV secreted by tumour cells. Here, we have shown that DDA differentiates tumour cells by acting on the LXRβ. This results in an increased production of sEV (DDA-sEV) which includes exosomes. The DDA-sEV secreted from DDA-treated cells were characterized for their content and activity in comparison to sEV secreted from control cells (C-sEV). DDA-sEV were enriched, relatively to C-sEV, in several proteins and lipids such as differentiation antigens, "eat-me" signals, lipidated LC3 and the endosomal phospholipid bis(monoacylglycero)phosphate, which stimulates dendritic cell maturation and a Th1 T lymphocyte polarization. Moreover, DDA-sEV inhibited the growth of tumours implanted into immunocompetent mice compared to control conditions. This study reveals a pharmacological control through a nuclear receptor of exosome-enriched tumour sEV secretion, composition and immune function. Targeting the LXR may be a novel way to reprogram tumour cells and sEV to stimulate immunity against cancer.
Insights
Dendrogenin A (DDA) promotes tumour cell differentiation and increases secretion of modified small extracellular vesicles (sEVs). These DDA-sEVs enhance anti-tumour immunity and inhibit tumour growth by modulating immune cell responses.
Area of Science:
- Oncology
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Tumour cells exhibit dedifferentiation and constitutively secrete small extracellular vesicles (sEVs), including exosomes.
- Dendrogenin A (DDA), a cholesterol-derived metabolite, acts as a tumour suppressor and a ligand for Liver X receptors (LXR).
- DDA is known to induce tumour cell differentiation, inhibit tumour growth, and promote immune cell infiltration.
Purpose of the Study:
- To investigate whether DDA can functionally modify the composition and activity of sEVs secreted by tumour cells.
- To explore the potential of DDA-modified sEVs in modulating anti-tumour immunity.
Main Methods:
- Tumour cells were treated with DDA to induce differentiation and alter sEV production.
- Small extracellular vesicles (sEVs) from DDA-treated (DDA-sEV) and control (C-sEV) cells were isolated and characterized.
- Proteomic and lipidomic analyses were performed on DDA-sEVs and C-sEVs.
- The anti-tumour activity of DDA-sEVs was evaluated in vivo using immunocompetent mice models.
Main Results:
- DDA treatment induced tumour cell differentiation via LXRβ, leading to increased sEV production (DDA-sEVs).
- DDA-sEVs were enriched in differentiation antigens, 'eat-me' signals, lipidated LC3, and bis(monoacylglycero)phosphate compared to C-sEVs.
- These specific components in DDA-sEVs promote dendritic cell maturation and Th1 T lymphocyte polarization.
- DDA-sEVs demonstrated significant inhibition of tumour growth in vivo.
Conclusions:
- Dendrogenin A (DDA) pharmacologically modulates exosome-enriched tumour sEV secretion, composition, and immune function through LXRβ.
- DDA-modified sEVs possess enhanced immunomodulatory properties, stimulating anti-tumour immunity.
- Targeting Liver X receptors (LXR) offers a novel strategy to reprogram tumour cells and their sEVs for cancer immunotherapy.
