Targeting the liver X receptor with dendrogenin A differentiates tumour cells to secrete immunogenic exosome‐enriched vesicles

Journal of Extracellular Vesicles

卷:11

Florence Bourgailh¹  Antonin Lamazière²  Vincent Lotteau³  Laure Perrin‐Cocon³  Marc Poirot⁴  Philippe de Medina⁴  Kevin Carayon⁴  Laly Pucheu⁴  Régis Soulès⁴  Bruno Payré⁴  Mehdi Attia⁴  Michel Record⁴  Julio Bunay⁴  Silia Ayadi⁴  Sandrine Silvente‐Poirot⁴ 

[1] Centre de Microscopie Electronique Appliquée à la Biologie Faculté de Médecine Rangueil Toulouse France;

[2] Sorbonne Université INSERM Centre de Recherche Saint‐Antoine CRSA AP‐HP.SU Hôpital Saint Antoine Département de métabobolomique clinique Paris France;

[3] Team “ VIRal Infection Metabolism and Immunity CIRI Centre International de Recherche en Infectiologie Univ Lyon Inserm U1111 Université Claude Bernard Lyon 1 CNRS UMR5308 ENS de Lyon Lyon France;

[4] Team “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;

关键词: bis(monoacylglycero)phosphate;    cancer;    cholesterol;    dendrogenin A;    differentiation;    exosomes;   

DOI  :  10.1002/jev2.12211

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown