Dendrogenin A reprograms tumor cells to secrete exosomes which activate the immune system against cancer

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), a natural cholesterol-derived antitumor molecule discovered in the team, is a ligand of the nuclear receptors LXR. Here, we have shown that DDA differentiates tumor cells by acting on the LXRβ. This results in an increased production of sEV which include exosomes (named DDA-exosomes). DDA-exosomes were enriched in several proteins and lipids such as differentiation antigens, “eat-me” signals, lipidated LC3 and the endosomal phospholipid BMP, which stimulates dendritic cell maturation and a Th1 T lymphocyte polarization. Moreover, DDA-exosomes inhibited the growth of tumors in vivo compared to control conditions. This study reveals that the targeting of LXRβ with DDA may be a novel way to reprogram tumor cells and exosomes to stimulate immunity against cancer.

The results obtained in this study open very important perspectives for the use of this molecule in the clinic since we will be able to identify the patients who will respond to DDA, due to the presence of the LXRβ receptor in the tumor, but also for the identification of immunogenic compounds within exosomes produced by DDA. Dendrogenin A could eventually be used as an immunotherapy target in oncology.

Targeting the LXRβ receptor with DDA, a natural metabolite of cholesterol, differentiates tumor cells to produce exosomes which stimulate immunity against tumor.

Collaborations and acknowledgements

Externals collaborations :

Laure Perrin-Cocon, Vincent Lotteau : 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.

Florence Bourgailh, Bruno Payré : Centre de Microscopie Electronique Appliquée à la Biologie, Faculté de Médecine Rangueil, Toulouse, France.

Antonin Lamazière : Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP.SU, Hôpital Saint Antoine, Département de métabobolomique clinique, Paris, France.

Financing :

PLBio 12-130/Institut National Du Cancer

PLBio 20-160/Institut National du Cancer (INCA)

Fondation Toulouse Cancer Santé