Extracellular vesicles, immune responses and cancer

Uriel Chantraine/Curie

Clotilde Théry Directeur de recherche INSERM Tel:

Cells release in their environment membrane-enclosed vesicles collectively called “Extracellular Vesicles” (EVs), which are thought to act as intercellular messengers. Exosomes are a type of EV formed inside endocytic compartments, the multivesicular bodies (MVBs) and secreted in vitro upon fusion of these MVBs with the plasma membrane. Other EVs, called microvesicles or ectosomes, are released by direct budding from the plasma membrane.

Figure 1 : Cells release various vesicles, which can either directly bud from the plasma membrane, or which form first inside intracellular multivesicular endosomes. These vesicles contain cytosolic components (proteins, nucleic acids), and expose at their surface the extracellular domain of the proteins and lipids of their limiting membrane. They have numerous functions, both for the homeostasis of the EV secreting cells, and as communication vehicle with their environment, local or distant. Cocozza, Grisard, Mathieu, Martin-Jaular, Théry, Cell 2020

Our group analyses the roles of exosomes and other EVs secreted by immune cells and tumor cells in immune responses established during tumor progression. Our goal is to identify the specific functions of each type of EV, to ultimately exploit their therapeutic or biomarker potential in cancer.

To do so, we combine 1) cell biology approaches and quantitative and comparative proteomic analysis to identify protein markers and molecular mechanisms of formation, secretion and interaction with target cells, specific to the different types of EVs, 2) the use of these molecular tools in tumor and immune cell models in vitro and in vivo, to understand how controlling the secretion and composition of different types of EVs can modify anti-tumor immune responses and tumor progression, 3) the analysis of EVs and their components as circulating biomarkers in breast cancer. We are also at the core of the EV research recommendations and best practice initiatives coordinated by the International Society of EVs (ISEV) (Thery*, Witwer*, J Extracell Vesicles 2018).

Our results in recent years include: identification of protein markers common to different EVs or specific to some (Kowal, PNAS 2016), demonstration that a protein used as a marker for EVs is instead a non-vesicular contaminant (Liao*, Martin-Jaular*, J Extracell Vesicles 2019), development of a novel unbiased approach to identify co-secreted proteins in EV subtypes and changes in these associations upon HIV infection (Martin-Jaular, EMBO J 2021). We have demonstrated that some immune functions are common to multiple EV subtypes, and others specific (Tkach, EMBO J 2017). We proposed the use of EVs as decoys for SARS-CoV-2 (Cocozza*, Nevo*, Piovesana*, J Extracell Vesicles 2020). We developed tools to quantify the capture and transfer of EV contents into the cytosol of target cells (Bonsergent, Nat Commun 2021).

Key publications

Year of publication 2020

Federico Cocozza, Eleonora Grisard, Lorena Martin-Jaular, Mathilde Mathieu, Clotilde Théry (2020 Jul 11)

SnapShot: Extracellular Vesicles.

Cell : 262-262.e1 : DOI : S0092-8674(20)30560-2

Year of publication 2019

Mathilde Mathieu, Lorena Martin-Jaular, Grégory Lavieu, Clotilde Théry (2019 Jan 4)

Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication.

Nature cell biology : 9-17 : DOI : 10.1038/s41556-018-0250-9

Year of publication 2018

Clotilde Théry, Kenneth W Witwer, Elena Aikawa, Maria Jose Alcaraz, Gregory Lavieu, ... Lorena Martin-Jaular, … Mathilde Mathieu, … Mercedes Tkach,… , Ewa K Zuba-Surma (2018 Nov 23)

Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines.

Journal of extracellular vesicles : 1535750 : DOI : 10.1080/20013078.2018.1535750

Year of publication 2017

Mercedes Tkach, Joanna Kowal, Andres E Zucchetti, Lotte Enserink, Mabel Jouve, Danielle Lankar, Michael Saitakis, Lorena Martin-Jaular, Clotilde Théry (2017 Sep 20)

Qualitative differences in T-cell activation by dendritic cell-derived extracellular vesicle subtypes.

The EMBO journal : DOI : e201696003

Year of publication 2016

Joanna Kowal, Guillaume Arras, Marina Colombo, Mabel Jouve, Jakob Paul Morath, Bjarke Primdal-Bengtson, Florent Dingli, Damarys Loew, Mercedes Tkach, Clotilde Théry (2016 Feb 8)

Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes.

PNAS : 113: E968-977 : DOI : 10.1073/pnas.1521230113

Year of publication 2015

Gentili M, Kowal 1, Tkach M, Satoh T, Lahaye X, Conrad C, Boyron M, Lombard B, Durand S, Kroemer G, Loew D, Dalod M, Théry C, Manel N. (2015 Jul 30)

Transmission of innate immune signaling by packaging of cGAMP in viral particles.

Science : DOI : 10.1126/science.aab3628
All publications