Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Exosomes, novel antigen bearers in "antitumor vaccination", yield some of their secrets

27.11.2002


Working model for the role of exosomes in immune responses.
After the uptake of incoming pathogens in the periphery, immature or maturing dendritic cells (green) generate peptide-MHC complexes. Some of these complexes could be secreted on exosomes, and locally sensitize other dendritic cells (blue) that have not encountered the pathogen directly. As a result of the effects of inflammation, all of these dendritic cells migrate out of the tissue towards the draining lymph nodes. Although maturing dendritic cells seem to secrete fewer exosomes than immature cells, an exchange of exosomes inside the lymph nodes between newly arrived (and not fully mature) and resident dendritic cells could take place also. Therefore, exosome production would increase the number of dendritic cells that bear the revelant peptide-MHC complexes, and thereby amplify the magnitude of immune responses. In the absence of inflammation, spontaneous migration of exosome-bearing dendritic cells could contribute to tolerance induction.


In this picture a mature dendritic cell (the cell on the right with dendrites) is moving towards a T lymphocyte (little rounded cell). The contact between a mature dendritic cell and a T lymphocytes is the initial step of an immune response.


Exosomes are minute, natural membrane vesicles secreted by various types of cells of the immune system. They are of enormous interest to oncologists, who are now using them in clinical trials as tumor-antigen bearers to trigger tumor rejection by the body.

On the basis of studies in vitro and in mice, INSERM doctors and research scientists at the Institut Curie proposed a novel mode of functioning of exosomes in the December 2002 issue of Nature Immunology. It seems that exosomes can indirectly stimulate the immune system. When they are secreted by dendritic cells (the immune system’s "sentries"), they are captured by other dendritic cells, which subsequently bring about the triggering of the immune response. It is as if one of the functions of the exosomes is to transfer their specific membrane-borne antigens to other dendritic cells, thus multiplying the number of "sentries" alerted and raising the defense potential of the immune system. If this mechanism is confirmed, it would partly explain how exosomes participate in tumor rejection in vivo.

These studies will undoubtedly lead to improvements in the use of antigen-bearing exosomes in cancer immunotherapy.



At the Institut Curie, a research group (Clotilde Théry, Sebastian Amigorena) and a medical team (Livine Duban, Olivier Lantz) (1) have joined forces to study the mechanisms of action of mouse dendritic cell-derived exosomes. At their surface these exosomes present several proteins involved in the stimulation of target T-cells (including molecules of the major histocompatibility complex or MHC), as well as a specific antigen. The Institut Curie teams confirmed that T-cells bearing a surface receptor to this specific antigen are directly stimulated in vivo, thus triggering the immune response. They noted, however, a strange phenomenon: exosomes only induce the proliferation of T-cells in vitro if "mature" dendritic cells are also present.

Do exosomes transfer antigens?

To explain this behavior, the authors propose that once they are produced the exosomes derived from "immature" dendritic cells will be captured by "mature" dendritic cells. The MHC-antigen complex is transferred from the exosomes to these dendritic cells, which then activate the appropriate T lymphocytes.

What is the benefit of such a strategy for the organism? The authors suggest that the exosomes may be secreted into the peripheral tissues where the dendritic cells meet pathogenic agents (viruses, bacteria, tumor cells) and migrate from there towards the lymph nodes where they sensitize mature dendritic cells. The exosomes could therefore "prime" several mature dendritic cells and hence increase the number of cells presenting the antigen to the T lymphocytes (diagram p.3). For the moment, however, this remains hypothetical since the secretion of exosomes by dendritic cells in vivo has not been formally demonstrated. In contrast, exosomes (first described almost 20 years ago) are clearly secreted in vitro.

What is important is that we can induce cells to secrete exosomes in vitro, i.e. in large quantities, and then use these exosomes to elicit in vivo specific immune reactions and not generalized activation of the immune system.

Highly characteristic but mysterious vesicles

Exosomes are flattened spheres, bounded by a lipid bilayer, that are secreted by the cell on the fusion of small internal compartments with the plasma membrane. They are smaller (30 to 100 nm in diameter) than other cell-secreted membrane vesicles.
The protein composition (internal or membrane) of exosomes is also characteristic and now quite well established: adhesion, transport, membrane fusion and signal transduction proteins, plus the proteins that bind and present the antigen. The precise function in the exosomes of most of these proteins remains unclear. The biological function of the exosomes themselves is also uncertain, although credible hypotheses can be built on the data accumulated in recent years.

Stimulatory activity and promising clinical trials

Several types of cells seem able to secrete exosomes, particularly certain cells of the immune system (mastocytes, T and B lymphocytes, dendritic cells, platelets).
In 1996, a pioneering team observed in vitro that exosomes derived from human B lymphocytes stimulate T lymphocytes, by presenting to them a specific antigen (2).

In 1998, a collaboration between scientists at the Institut Curie and the Institut Gustave-Roussy showed that exosomes, produced in vitro by dendritic cells previously pulsed with tumor antigens, induce tumor rejection in mice (3).

One of the lines of research then focused on the use of these exosomes as a "vaccine" in the prevention of tumor recurrence caused by cancer cells that elude the effects of treatment.

After the positive findings recorded in mice, a first phase I clinical trial (to determine toxicity and effective dose in a small number of patients) was launched in France in 2000, at the Institut Curie and at the Institut Gustave-Roussy. Exosomes bearing the melanoma antigen MAGE3 were administered to patients with metastatic melanoma expressing MAGE3. No toxicity was seen, but there was a positive response in the patients receiving the highest doses: regression of skin tumors in some and reduction of lymph node metastases in others.

A second phase I clinical trial is currently under way in the United States, at Duke University. Dendritic cell-derived exosomes are being administered to patients with non-small cell lung cancer. The preliminary results show prolonged stabilization of the disease.
Another phase I trial should begin in France in 2003, using exosomes in the treatment of cancer of the neck of the womb.

Finally, the American authorities have just approved a planned Franco-American, multicenter (Institut Curie, Institut Gustave-Roussy and several American hospitals) phase II trial in patients with advanced melanoma or non-small cell lung cancer.


Reference

"Indirect activation of naïve CD4+T cells by dendritic cell-derived exosomes"
Clotilde Théry*, Livine Duban*°, Elodie Segura*, Philippe Véron*, Olivier Lantz*° and Sebastian Amigorena*
Nature Immunology, vol 3, no. 12, December 2002
* Unité INSERM 520, Institut Curie. ° Laboratoire d’Immunologie Préclinique, Institut Curie

Notes

(1) Unité INSERM 520 "Cellular biology of tumoral immunity" headed by Christian Bonnerot, Research division of Institut Curie and Preclinical Immunology Laboratory, Medical division of Institut Curie.
(2) "B lymphocytes secrete antigen-presenting vesicles" Raposo, G., Nijman, H.W., Stoorvogel, W., Liejendekker, R., Harding, C.V., Melief, C.J. and Geuze, H.J. Journal of Experimental Medicine. Vol 183, 1161-72, 1996
(3) "Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes" L. Zitvogel, A. Regnault, A. Lozier, J. Wolfers, C. Flament, D. Tenza, P. Ricciardi-Castagnoli, G. Raposo & S. Amigorena - Nature Medicine, Vol.4, No. 5, 594-600, May 1998

Press contacts

Institut Curie
Press Office
Catherine Goupillon
Phone 01 44 32 40 63
service.presse@curie.fr

Iconography
Cécile Charré
Phone 01 44 32 40 51
Fax 01 44 32 41 67

Inserm
Press Center
Céline Goupil
Phone 01 44 23 60 73
presse@tolbiac.inserm.fr

Séverine Ciancia
Phone 01 44 23 60 86

Catherine Goupillon | Institut Curie

More articles from Life Sciences:

nachricht Rainbow colors reveal cell history: Uncovering β-cell heterogeneity
22.09.2017 | DFG-Forschungszentrum für Regenerative Therapien TU Dresden

nachricht The pyrenoid is a carbon-fixing liquid droplet
22.09.2017 | Max-Planck-Institut für Biochemie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: The pyrenoid is a carbon-fixing liquid droplet

Plants and algae use the enzyme Rubisco to fix carbon dioxide, removing it from the atmosphere and converting it into biomass. Algae have figured out a way to increase the efficiency of carbon fixation. They gather most of their Rubisco into a ball-shaped microcompartment called the pyrenoid, which they flood with a high local concentration of carbon dioxide. A team of scientists at Princeton University, the Carnegie Institution for Science, Stanford University and the Max Plank Institute of Biochemistry have unravelled the mysteries of how the pyrenoid is assembled. These insights can help to engineer crops that remove more carbon dioxide from the atmosphere while producing more food.

A warming planet

Im Focus: Highly precise wiring in the Cerebral Cortex

Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.

The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...

Im Focus: Tiny lasers from a gallery of whispers

New technique promises tunable laser devices

Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...

Im Focus: Ultrafast snapshots of relaxing electrons in solids

Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!

When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...

Im Focus: Quantum Sensors Decipher Magnetic Ordering in a New Semiconducting Material

For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.

Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

“Lasers in Composites Symposium” in Aachen – from Science to Application

19.09.2017 | Event News

I-ESA 2018 – Call for Papers

12.09.2017 | Event News

EMBO at Basel Life, a new conference on current and emerging life science research

06.09.2017 | Event News

 
Latest News

Rainbow colors reveal cell history: Uncovering β-cell heterogeneity

22.09.2017 | Life Sciences

Penn first in world to treat patient with new radiation technology

22.09.2017 | Medical Engineering

Calculating quietness

22.09.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>