Extracellular vesicles, immune responses and cancer

Théry

Clotilde Théry Team Leader 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.

Our group analyses the roles of exosomes and other EVs secreted by immune cells (especially dendritic cells) and tumor cells in the immune responses established during tumor progression, with a view to evaluate the therapeutic potential of exosomes and/or EVs in cancer.

Figure 1 : Cells release various vesicles, using different intracellular machineries. Kowal, Tkach and Théry, Curr Op Cell Biol 2014.
Figure 1 : Cells release various vesicles, using different intracellular machineries. Kowal, Tkach and Théry, Curr Op Cell Biol 2014.

Fifteen years ago, we had initiated proteomic analyses of the composition of exosomes secreted by dendritic cells. We have shown that these EVs are distinct from EVs isolated from apoptotic cells, and thus are the result of an active process of secretion by live cells (Théry et al, J Cell Biol 1999, J Immunol 2011). Furthermore, we showed that exosomes secreted by dendritic cells bear antigen and MHC-peptide complexes and thus participate in induction of immune responses (Théry et al, Nature immunol 2002), especially when secreted by mature DCs (Segura et al, Blood 2005, J Immunol 2007). We also showed that forcing secretion of an antigen on their exosomes by tumors promoted induction of anti-tumor immune responses (Zeelenberg et al, Cancer Res 2008). Our results have been used to design a phase II clinical trial, at Institut Gustave Roussy and Institut Curie, using exosomes produced by mature dendritic cells from cancer patients as maintenance immunotherapy (Besse et al, Oncoimmunology, in press).

We have also analysed the role in tumor progression of one of the major components of tumor cell- and mouse dendritic cell-derived EVs, called MFGE8/lactadherin. We observed that MFGE8 promotes VEGF-mediated angiogenesis (Silvestre, Théry et al, Nature Med 2005), bladder tumor progression via an effect on the host immune system (Sugano et al, Oncogene 2011), and survival and migration of ovarian cancer cells (Tibaldi et al, Plos One 2013). MFGE8 thus represents a potential target for novel anti-tumor therapies.

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Figure 2: Overall composition of extracellular vesicles. Colombo, Raposo and Théry, Ann Rev Cell Dev Biol 2014

In the last 5 years, we have focused our research on the molecular mechanisms of biogenesis and secretion of the different types of EVs, with a goal to find specific tools to affect their selective secretion, and thus understand their respective roles in tumor progression, and their potential use as targets or biomarkers in cancer. We have initially identified RAB27 small GTPases as required for exosome secretion by tumor cells, and used it to show an in vivo pro-tumoral role of exosome secretion by a murine tumor, although inhibition of exosome secretion by another tumor did not affect its progression.

Our cell biology studies have now evidenced the heterogeneity of the EVs secreted by dendritic and tumor cells, and we are currently focusing on unravelling their respective composition, including their differences and similarities with enveloped viruses, their immune functions, and the best ways to isolate and/or affect specifically secretion of the different EV subtypes.

 

 

Key publications

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

Year of publication 2014

Christine Sedlik, James Vigneron, Lea Torrieri-Dramard, Fabien Pitoiset, Jordan Denizeau, Caroline Chesneau, Philippe de la Rochere, Olivier Lantz, Clotilde Thery, Bertrand Bellier (2014 Aug 27)

Different immunogenicity but similar antitumor efficacy of two DNA vaccines coding for an antigen secreted in different membrane vesicle-associated forms.

Journal of extracellular vesicles : DOI : 10.3402/jev.v3.24646

Year of publication 2013

Lorenzo Tibaldi, Shirley Leyman, André Nicolas, Sofie Notebaert, Melissa Dewulf, Thu Hoa Ngo, Claudia Zuany-Amorim, Nathalie Amzallag, Isabelle Bernard-Pierrot, Xavier Sastre-Garau, Clotilde Théry (2013 Aug 16)

New blocking antibodies impede adhesion, migration and survival of ovarian cancer cells, highlighting MFGE8 as a potential therapeutic target of human ovarian carcinoma.

PloS one : e72708 : DOI : 10.1371/journal.pone.0072708

Year of publication 2012

Angélique Bobrie, Sophie Krumeich, Fabien Reyal, Chiara Recchi, Luis F Moita, Miguel C Seabra, Matias Ostrowski, Clotilde Théry (2012 Aug 3)

Rab27a supports exosome-dependent and -independent mechanisms that modify the tumor microenvironment and can promote tumor progression.

Cancer research : 4920-30 : DOI : 10.1158/0008-5472.CAN-12-0925
All publications