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Month: February 2022

Discovery of an innate immunological memory in the intestine

Posted on by Graziella Cara

ILC3 intestinales

Intestinal ILC3s. Immunofluorescence staining of ILC3s (green) in the intestine (nuclei in blue and actin in red). © Nicolas Serafini – Institut Pasteur / Inserm

The innate immune system plays a crucial role in regulating host-microbe interactions, and especially in providing protection against pathogens that invade the mucosa. Using an intestinal infection model, scientists from the Institut Pasteur and Inserm discovered that innate effector cells – group 3 innate lymphoid cells – act not only during the early stages of infection but can also be trained to develop an innate form of immunological memory that can protect the host during reinfection. The study was published in the journal Science on February 25, 2022.

Combating Escherichia coli infections, which are responsible for intestinal diseases or gastrointestinal bleeding, is a major public health challenge. These bacteria, which are present in drinking water or food, can cause persistent diarrhea associated with acute intestinal inflammation. Consequently, enteropathogenic and enterohemorrhagic Escherichia coli are responsible for nearly 9% of child deaths worldwide.

The gut mucosa harbors a complex defense system that allows it to combat pathogen infection while maintaining tolerance to commensal microbiota, which are essential for the normal bodily function. This constant surveillance is performed by the innate immune system, which provides early defense in the initial hours after infection.

The adaptive immune system then develops a memory for the pathogens that it encounters by activating specific receptors expressed at the surface of B and T lymphocytes, thereby enabling the production of protective antibodies and inflammatory cytokines. Unlike the clearly established function of the adaptive system in long-term tolerance and protection, the role of the innate system in immune memory remains to be determined.

In 2008,[1] the team led by Inserm scientist James Di Santo (Innate Immunity Unit, Institut Pasteur/Inserm) described group 3 innate lymphoid cells (ILC3s) as a novel family of lymphocytes that were distinct from adaptive T and B lymphocytes. ILC3s play an essential role in the innate immune response, especially in the gut mucosa, by producing pro-inflammatory cytokines, such as interleukin (IL)-22.

The cytokine release activates the production of antimicrobial peptides by epithelial cells, thereby reducing the bacterial load in order to maintain the integrity of the intestinal barrier.

In this study, scientists from the Innate Immunity Unit (Institut Pasteur/Inserm) used an innovative protocol to expose the immune system to a time-restricted enterobacterial challenge based on Citrobacter rodentium (a mouse model of E. coli infection). They observed that ILC3s persist for several months in an activated state after exposure to C. rodentium.

During a second infection, the “trained” ILC3s have a superior capacity to control infection through an enhanced proliferation and massive production of IL-22.

“Our research demonstrates that intestinal ILC3s acquire a memory to strengthen gut mucosal defenses against repeated infections over time,” explains Nicolas Serafini, first author of the study and an Inserm scientist in the Innate Immunity Unit (Institut Pasteur/Inserm).

“The ability to “train” the innate immune system in the mucosa paves the way for improvements to the body’s defenses against a variety of pathogens that cause human diseases,” comments James Di Santo, last author of the study and Head of the Innate Immunity Unit (Institut Pasteur/Inserm).

This discovery demonstrates a new antibacterial immune defense mechanism and could lead, in the long term, to novel therapeutic approaches to treat intestinal diseases (IBD or cancer).

 

[1] Satoh-Takayama N. et al. Immunity 2008

Better Understanding the Role of a White Blood Cell Type in SARS-CoV-2 Immune Response

Posted on by Graziella Cara

cellule basophile

Image of a basophil showing the granules (dark circles) characteristic of granulocytes. ©Inserm/Janine Breton-Gorius

Although the response of various immune cells to SARS-CoV-2 infection has been relatively well studied, that of basophils (a category of white blood cells) had not been characterized yet – mainly because of their rarity in that they represent around 0.5% of the body’s white blood cells. In a new study, researchers from Inserm, Sorbonne Université, Université de Paris, CNRS, Institut Pasteur and Efrei describe how basophils respond to SARS-CoV-2 infection. They show that exposure to the virus activates them, leading to the production of certain cytokines and helping to reduce inflammation and promote the secretion of antibodies. The findings of this study were published in Frontiers in Immunology on February 24, 2022.

Basophils are leukocytes (white blood cells) that play a key role in immune response. They are produced in the bone marrow and make up around 0.5% of all leukocytes. In addition to their role in protecting against parasitic infections, basophils are involved in the response to various allergic inflammatory diseases of the respiratory tract (allergic rhinitis, asthma), gastrointestinal tract (food allergies), and the skin (atopic dermatitis).

Previous studies have evaluated the role of immune system cells known as granulocytes

– neutrophils, eosinophils, and basophils – in the immune response to SARS-CoV-2 infection. These findings had revealed a smaller number of basophils during the acute and severe phases of COVID-19, followed by an increase in their number up to the disease recovery phase, four months after discharge from hospital. These same basophils were also “activated”: they produced cytokines, molecules enabling communication between immune cells and capable of adapting the immune response to the nature of the infectious agent.

Through in vitro studies of the reaction of healthy basophils exposed to SARS-CoV-2, a team of researchers from Inserm, Sorbonne Université and Université de Paris at the Cordeliers Research Center, from CNRS and Institut Pasteur at the Evolutionary genomics, modeling and health laboratory, and from Efrei wished to describe the cytokine response of basophils more precisely. It observed that the activation of basophils resulted in the production of specific cytokines, known as interleukins IL-4 and IL-13.

These interleukins allow basophils to interact with the other immune cells, especially the T and B cells, and to establish a link between innate and adaptive immunity (see box). For example, IL-4 directs B cells towards the production of antibodies.

Basophils such as neutrophils and eosinophils are innate immune cells, whereas B and T cells are adaptive immune cells.

Innate immunity is an immediate response that occurs in any individual in the absence of prior immunization. It is the first barrier of defense against various pathogens and mainly brings into play pre-formed (natural) antibodies and lymphocytes that do not present receptors specific to the antigen.

Adaptive immunity is established a few days after contact with the pathogen and is the body’s second line of defense. Unlike innate immunity, adaptive immunity is specific for a given antigen.

Furthermore, the scientists have also shown that when basophils are stimulated by interleukin IL-3, itself produced by the T cells, they produce more IL-4 and IL-13.

These data highlight the potentially beneficial role of IL-3 in COVID-19 patients. Other research findings had already shown that low IL-3 levels in the plasma of patients infected with SARS-CoV-2 were associated with greater severity of the disease.

“More generally, these findings deepen the little scientific knowledge we had until now on the key role played by basophils in immune response and in the context of viral infections. The mechanism by which SARS-CoV-2 induces basophil activation is now the subject of new research,” explains Camille Chauvin, Inserm researcher and co-author of the study.

“Whereas other studies have shown the pathological role of innate cells such as neutrophils, monocytes and macrophages activated by SARS-CoV-2, we found potential beneficial effects of the activation of basophils by the virus. Being able to modulate basophil activation, via IL-3 for example, could potentially allow us to regulate the protective antibody response to a viral infection such as SARS-CoV-2,” concludes Jagadeesh Bayry, Inserm Research Director and last author of the study.

Transplantation chemotherapy eliminates regenerative capacity of brain’s innate immune cells

Posted on by Graziella Cara

Brain microglia (green) initiating expression of cell division marker (red), but unable divide due to co-expression of a senescence marker (blue), due to the chemotherapy treatment (busulfan). © K. Sailor/ PM Lledo, Institut Pasteur.

Annually over 50,000 bone marrow transplantations occur worldwide as a therapy for multiple cancerous and non-cancerous diseases. Yet, how this procedure gives rise to bone marrow-derived cells that engraft the brain, despite being absent in the normal brain, remains unknown. In the present study, scientists from the Institut Pasteur, the CNRS and the Paris Brain Institute (Inserm) discovered how the host’s microglia, the brain’s innate immune cells, are replaced by bone marrow-derived macrophages. The key discovery was that transplantation chemotherapy eliminated the microglia’s regenerative capacity, gradually causing the engraftment of macrophages to replace microglia, providing a potential mechanism for future cell-based therapies to treat central nervous system diseases. This finding will be published in Nature Medicine on February 21, 2022.

Progressive demyelination of the central nervous system leads to devastating neurologic symptoms and premature death. As the number of cases diagnosed through pregnancy and newborn screening is increasing, more efficient therapeutic strategies are required. Recently, the successful use of gene therapy to correct disease-causing gene mutations in bone marrow stem cells, and their subsequent autologous transplantation into patients, has been clinically used for treating white matter diseases, while eliminating the need for finding matching donors. Clinical studies showed that pre-transplantation ablation of host bone marrow stem cells using the chemotherapy agent busulfan allows for efficient engraftment and tolerance to gene-modified cells, yet the mechanism involved was largely known.

Using an animal model, neuroscientists from the Institut Pasteur (CNRS) and the Paris Brain Institute (Inserm) have demonstrated the broad impact of busulfan chemotherapy used for bone marrow transplant therapy on various cell populations of the host brain.

Microglia are tissue-resident brain immune cells that are instrumental for maintaining healthy brain physiology in normal and diseased states. These cells exhibit a robust self-renewal capacity and gradually turnover throughout life. However, in this study, Sailor and colleagues show that following pre-transplantation busulfan chemotherapy, microglia completely lose their regenerative capacity, becoming senescent, which thereby allowed the engraftment of bone marrow-derived macrophages into the brain. They also show these macrophages to become resident with similar surveillant dynamics as the microglia they replaced.

They demonstrate that busulfan administration temporarily depleted oligodendrocyte precursor cells and, importantly, caused the complete and permanent ablation of all adult neurogenesis, which may explain cognitive deficits in patients after busulfan chemotherapy, i.e. the “chemo brain”. Microglia that were eliminated because of busulfan chemotherapy, coupled with their loss of regenerative capacity, leave empty niches in the brain which are replaced by engrafted bone marrow-derived macrophages. These macrophages assumed the morphology and cellular process dynamics like normal microglia.

This study is highly relevant since for the first time it shows a mechanism dependent on microglia senescence, with the loss of their regenerative capacity, to explain how macrophages are permissively engrafted into the brain after bone marrow transplantation.

Furthermore, this work shows multiple off-target effects of bone marrow transplantation chemotherapy, which may be important for understanding post-chemotherapy cognitive issues. Understanding the mechanism of peripheral macrophage engraftment is imperative to develop further cell-based gene therapy strategies for central nervous system diseases.

“Microglial cells play an essential role in brain function and in the pathophysiology of many severe neurological diseases, both genetic and complex, such as multiple sclerosis and Alzheimer’s disease. Understanding the fate of these cells after the transplant process is essential both to clarify the consequences of chemotherapy and to develop new therapeutic strategies for serious neurodegenerative diseases,” said Nathalie Cartier, research director at Inserm and member of the NeuroGenCell team at the Brain Institute (ICM), and last co-author of the study.

“This study sheds light for the first time on a mechanism explaining how stem cell-derived macrophages enter the brain after bone marrow cell transplantation. This better understanding is essential to develop new strategies for gene and cell therapy applied to diseases of the central nervous system,” said Pierre-Marie Lledo, research director at the CNRS and head of the Perception and Memory Unit at the Institut Pasteur, and last co-author of the study.

“We show bone marrow transplantation chemotherapy to cause microglia, the brain’s resident immune cells, to lose their regenerative capacity. The microglia were unable to sustain their population which allowed bone marrow derived cells to replace them. This demonstrates how bone marrow transplantation is an effective therapy for certain neurological diseases and provides a strategy for cellular gene therapy in the central nervous system,” said Kurt Sailor, research fellow at the Institut Pasteur Unit Perception and Memory in Paris, and first author of the study.

Defeating leukaemia cells by depriving them of energy

Posted on by Graziella Cara

Cellules leucémiques

Selective activation of the AMPK enzyme would lead to the death of leukaemia cells (in purple in this image). © Jérôme Tamburini / UNIGE High resolution pictures


A Swiss-French team that includes UNIGE scientists has discovered how to trigger apoptosis in leukaemia cells by disrupting their energy maintenance mechanism.

Acute myeloid leukaemia, which affects blood and bone marrow cells, is a particularly dangerous form of cancer. More than half of patients under the age of 60 die. This proportion rises to 85% for patients over 60. A team from the University of Geneva (UNIGE), Switzerland, and from Inserm 1, in France, have identified a previously unknown mechanism that could lead to the development of new therapies. The selective activation of AMPK, a key enzyme in the energy balance of tumour cells, would indeed lead to their death by triggering the cells stress response. Moreover, the scientists have successfully exploited this energy gap in an animal model of the disease: a combination of two drugs — one of which is already on the market — has indeed shown promise. However, their effectiveness has yet to be confirmed on leukaemia stem cells, which have the ability to escape many treatments to restart tumour growth. These results can be found in the journal Cell Reports.

Jérôme Tamburini, an associate professor in the Department of Medicine and in the Translational Research Centre in Onco- Haematology (CRTOH) of UNIGE Faculty of Medicine and at the Swiss Cancer Center Léman (SCCL) and a professor at Université de Paris, is working on the energetic mechanisms of tumour cells in acute myeloid leukaemia. A cell signalling pathway called AMPK is of particular interest to him. “AMPK is the main detector of the cells energy level”, explains Jérôme Tamburini. “This pathway is activated when energy is lacking and initiates the degradation of certain nutrients to produce the necessary energy – a process called catabolism. As without energy, no cell can survive, could it be possible to selectively manipulate this mechanism in tumour cells to cause their destruction, while preserving healthy cells?” In 2015, Jérôme Tamburini and his colleagues at Inserm in Paris participated in the development with the GlaxoSmithKline (GSK) laboratory of a pharmacological component — GSK621 — which proved to be an excellent activator of AMPK in vitro. “After this initial proof of principle, we had to decipher the biochemical mechanisms at work in order to understand them in detail, and in particular which cellular pathways did GSK621 activate in leukaemia cells, the first step in hoping to exploit this phenomenon for therapeutic purposes,” explains Jérôme Tamburini.

An effective combination of two drugs

The first step was to perform a gene expression analysis of human tumour cells, which identified an enzyme, PERK, particularly activated in response to the presence of GSK621.This is a key element in the stress response of the endoplasmic reticulum, an intracellular structure specialised in the metabolism of proteins and lipids. “The activation of AMPK thus triggers the activation of PERK, followed by a chain of reactions leading to apoptosis, the programmed death of the cell,” explains Jérôme Tamburini. “In addition, the activation of AMPK by GSK621 sensitises the cells to the effects of another pharmacological drug, the venetoclax, which is now widely used to treat acute myeloid leukaemia, although with limited effectiveness when used alone.”

The scientists then combined the two drugs in mice carrying human tumour cells, and found that this combination controlled tumour development much more effectively than in monotherapy. While GSK621 was not designed to be a drug, other products are currently in clinical trials to combat metabolic diseases, which activate the AMPK pathway. “Understanding the mechanism involved has brought to light potential therapeutic targets that were previously unknown,” explains Jérôme Tamburini. “We will now be able to review all the drugs known to have an effect on these pathways and determine which combinations would be the most effective.”

What about leukaemic stem cells?

Leukaemic stem cells consists in a small population of cells within the tumour that can only be detected by their ability to spread again the tumour after an initially successful treatment. The main cause of relapse, these cells are sensitive to very few of the therapies usually used in leukaemia. Furthermore, evidence is still lacking to determine the effect that massive activation of AMPK would have on them. “Before testing drug combinations targeting this AMPK/PERK mechanism in human beings, we need to determine their effeleukaemic stem cells,” the authors conclude.

 

1. Several laboratories were involved, including Institut Cochin (Inserm/CNRS/University of Paris), the Cancer Research Center of Lyon (Inserm/CNRS/Claude Bernard Lyon 1 University/ Léon Bérard Centre) and the Toulouse Cancer Research Center (Inserm/CNRS/Toulouse III –Paul Sabatier University)

A Novel Immunotherapy Approach Redirects Epstein-Barr Antibodies toward Disease-Causing Cells

Posted on by Léa Surugue

Microscopic visualization of a cancerous cell (nucleus in blue) treated with bi-modular fusion proteins (BMFPs) to which EBV antibodies (green) bind. © Jean-Philippe Semblat and Arnaud Chêne – JRU1134 (Inserm/Université de Paris)

 

Monoclonal antibody therapy can be very effective in treating numerous illnesses, such as cancers, chronic inflammatory conditions, and infectious diseases. However, it is costly and uses molecules that are complicated to produce. Therefore, it is essential to identify new therapeutic alternatives so that as many patients as possible get the treatments they need. That is why researchers from Inserm, Université de Paris, Sorbonne Université and CNRS1 have designed and tested a new immunotherapy approach that uses pre-existing antibodies directed against the Epstein-Barr virus – part of the herpes family of viruses and present in over 95% of the world’s population – in order to target and destroy pathogenic (disease-causing) cells. Their findings have recently been published in a study in Science Advances.

The principle is to redirect a pre-existing immune response against the Epstein-Barr virus (EBV) to target cells that we wish to destroy. The Epstein-Barr virus – which belongs to the family of herpes viruses – is transmitted predominantly through saliva, and over 95% of the world’s population is infected with it.

The vast majority of people have no symptoms, and the virus has the ability to persist chronically in infected individuals under the effective control of the immune system. As a result, EBV antibodies circulate in these people throughout their lives.

Developing a therapeutic tool based on the recruitment of these pre-existing EBV antibodies is of major interest in redirecting this immune response against target cells that are predefined according to the disease in question. This immunotherapy may be applicable in a very large number of patients due to the presence of EBV antibodies in almost everyone.

A promising new system

The researchers have developed specific proteins called bi-modular fusion proteins (BMFPs). These possess a domain that will bind specifically to an antigen expressed on the surface of the target cell to be destroyed. This domain is also fused to the Epstein-Barr virus EBV-P18 antigen against which IgG2 antibodies are already present in the patient. The recruitment of these antibodies on the surface of the target cells treated with BMFPs will then activate the body’s immune defenses, leading to the destruction of the target cells.

The researchers first tested this system in vitro using several target cells and showed that it effectively triggers different immune system mechanisms capable of eliminating target cells.

The BMFPs were then engineered to target an antigen expressed on the surface of tumor cells and were tested in an animal model of cancer. The results are promising because the treatment led to a significant increase in survival as well as the complete remission of cancer in some animals.

“These results position BMFPs as novel therapeutic molecules that may be useful in the treatment of multiple diseases. It is a highly versatile system, since it is easy to change the binding module and as such the antigen targeted in order to adapt the treatment to many diseases, in oncology, infectious diseases, and also autoimmune conditions,” explains Arnaud Chêne, Inserm Research Officer and last author of the study.

“BMFPs are much easier and faster to produce than whole monoclonal antibodies and do not require the use of sophisticated engineering to optimize their functions, thereby reducing costs and opening up access to a broader spectrum of patients,” adds Jean-Luc Teillaud, Emeritus Research Director at Inserm.

“Pending clinical trials in a variety of diseases ranging from cancer to malaria, the technology has already led to the filing of two patents.” explains Benoît Gamain, Research Director at CNRS.

 

1 Two laboratories took part in this research: Integrated Red Blood Cell Biology (U1134 Inserm/Université de Paris) and Center for Immunology and Microbial Infection (U1135 Inserm/Sorbonne Université/CNRS).

2 IgGs represent the main type of antibody found in the blood and are involved in the secondary immune response

A Gene Therapy Studied in Steinert’s Disease

Posted on by Léa Surugue

Steinert’s disease is caused by the abnormal repetitions of a small DNA sequence in the DMPK gene. ©Unsplash

Myotonic dystrophy type 1 (DM1) or Steinert’s disease is a rare and debilitating genetic neuromuscular disease affecting multiple organs and with a fatal outcome. No treatment is available at present. Encouraged by previous research into its molecular causes, researchers from Inserm, CNRS, Sorbonne Université, Lille University Hospital and Université de Lille, in partnership with the Institute of Myology, at the Center for Research in Myology and the Lille Neuroscience & Cognition center, have developed and tested a promising gene therapy that acts directly at the origin of the disease. Initial findings published in Nature Biomedical Engineering show correction of molecular and physiological alterations in mouse skeletal muscle1.

Myotonic dystrophy type 1 (DM1), otherwise known as Steinert’s disease, is a rare, hereditary and genetic neuromuscular condition affecting around 1 in 8,000 people. Debilitating and fatal, it is referred to as a “multisystem” condition because it simultaneously affects the muscles (muscle weakening and atrophy called “dystrophy”; muscle relaxation impairment called “myotonia”) and other organs (cardiorespiratory, digestive and nervous systems, etc.). The expression and course of the disease vary from one patient to the next and no treatment exists as yet.

It is caused by the abnormal repetition of a small DNA sequence (triplet CTG2) in the DMPK (DM1 Protein Kinase) gene located on chromosome 19. In healthy individuals, this sequence is present but repeated between 5 and 37 times. However, in patients with DM1, a mutation occurs whereby the number of triplets increases, producing up to several thousand repetitions.

About the mechanisms enabling gene expression

To obtain the production of a protein, a gene (located in the cell nucleus) is first transcribed into a molecule of RNA. To become a messenger RNA (mRNA), it undergoes maturation, particularly involving splicing. This basically means that the molecule is cut into pieces, some of which are eliminated and others attached. Thanks to this finely regulated process, one gene can lead to the synthesis of different mRNA and therefore of different proteins. After splicing, the mature mRNA will eventually be translated into protein, outside of the cell nucleus.

In Steinert’s disease, the mutated gene is transcribed but the mutant mRNA are retained in the cell nuclei as characteristic aggregates. In the cells of people with DM1, the MBNL1 proteins that normally bind to certain RNA in order to regulate their splicing and maturation are “captured” by the RNA that carry the mutation.

Thus sequestered in the aggregates, it is impossible for them to perform their functions, resulting in the production of proteins that function less well or not at all, some of which have been linked to clinical symptoms.

The team led by CNRS Research Director Denis Furling at the Myology Research Center (Inserm/Sorbonne Université/Institute of Myology) in association with that of Nicolas Sergeant, Inserm Research Director at the Lille Neuroscience & Cognition Centre (Inserm/Université de Lille/Lille University Hospital), focused on a therapeutic strategy to restore the initial activity of MBNL1 in skeletal muscle cells expressing the mutation responsible for Steinert’s disease.

To do this, the scientists engineered modified proteins that present, like the protein MBNL1, binding affinities for the RNA carrying the mutation and as a consequence act as a decoy for these RNA.

When expressing these decoy proteins in vitro in muscle cells from patients with DM1, they observed that they were captured by the mutated RNA instead of the MBNL1 proteins. The latter were then released from the aggregates of mutated RNA and regained their normal function. As a result, the splicing errors initially present in these cells disappeared. Finally, the mutated RNA bound to the decoy proteins proved to be less stable and could be more easily and effectively eliminated by the cell.

Aggregates of mutant DMPK-RNA containing pathological triplet (red) repetitions visualized by FISH-immunofluorescence in the nuclei (blue) of muscle cells (green) isolated from patients with Myotonic dystrophy type1 © Denis Furling and Nicolas Sergeant

The research team then transposed this technique into an animal model in order to verify the validity of this approach in vivo. With the help of viral vectors used in gene therapy, the decoy proteins were expressed in the skeletal muscle of mouse models of Steinert’s disease. In these mice, a single injection was effective, over a long period of time and with few side effects, in correcting the muscle damage associated with the disease, particularly the splicing errors, myopathy and myotonia.

“Our findings highlight the efficacy on Steinert’s disease symptoms of a gene therapy based on the bioengineering of RNA-binding decoy proteins with strong affinity for the pathological repetitions present in the mutated RNA, in order to release the MBNL1 proteins and restore their regulatory functions,” declares Furling. However, the authors point out that additional studies are needed before this therapy can be transposed into a clinical study. “This research paves the way for the development of therapeutic solutions in the context of other diseases in which pathological RNA repetitions cause splicing regulation dysfunction,” concludes Sergeant.

 

1 The striated skeletal muscle is the muscle that is attached to the skeleton by tendons and which, due to its ability to contract, enables the performance of precise movements in a well-defined direction.

2 The coding sequence of a gene consists of the chaining of different combinations of four nucleic acids: adenine, guanine, cytosine, and thymine (replaced by uracil in RNA). These are organized in triplets (or codons) whose correct “reading” by the cell machinery enables the expression of a protein.

Signature du premier contrat d’objectifs de moyens et de performance entre l’Inserm et l’État

Posted on by Tatiana Marotta

Signing of the Contract of Objectives, Means and Performance between the French State and Inserm on February 4, 2022, in the presence of Frédérique Vidal – Minister of Higher Education, Research and Innovation, Olivier Véran – Minister of Solidarity and Health, and Gilles Bloch – Inserm CEO. © Inserm

“A new impetus for health biology research.” This is the ambition of Inserm’s Contract of Objectives, Means and Performance signed on Friday, February 4, 2022 by Frédérique Vidal – Minister of Higher Education, Research and Innovation, Olivier Véran – Minister of Solidarity and Health, and Gilles Bloch – Inserm CEO.

This contract consolidates a shared vision of biomedical research and more particularly of Inserm’s roadmap for the coming years, as well as the commitment to make it a reality. It falls within the scope of Inserm’s missions and the strategic orientations defined by its supervisory bodies – particularly the research programming law, the national health strategy, and the “France 2030” investment plan.

At the event, Gilles Bloch was keen to thank the ministers “for their continued confidence in Inserm, emphasizing that this new contract gives Inserm the means to sustain its ambition of research excellence serving innovation and health for all citizens. “

Due to its size, broad spectrum of activities and renowned expertise, Inserm plays a pivotal role in structuring and guiding French biomedical research, in conjunction with its ministerial supervisory bodies in research and health. Its activity makes Inserm Europe’s leading public institution in the field of health research. The challenges at stake in this contract between the State and Inserm are to produce world-class science, cultivate fertile ground for future major biomedical discoveries, and best serve the health of all citizens.

The ambition of Inserm’s Contract of Objectives, Means and Performance falls in line with the priorities of France’s research programming law (LPR).

It also reflects the priority given to public health and prevention and shares the same objectives as the research component of the national health strategy, whether in terms of knowledge development, support of medical, technological and organizational innovations, or the acceleration of digital innovation.

Finally, this contract reflects Inserm’s 2020-2025 Strategic Plan in operational terms and sets out the following four priorities, with which it associates actions and resources:

  1. Reinforce the health research continuum while promoting disruptive research
  2. Increase Inserm’s ability to implement its choices in synergy with its public and private partners, in France, Europe and internationally
  3. More effectively support laboratories by revamping the human resources policy and simplifying administrative procedures
  4. Speed up the development of open, responsible science and reinforce the role of health sciences in our society

The SARS-CoV-2 pandemic has highlighted the importance of responsive and coordinated research across the entire biomedical research and public health continuum – which has been a priority of Inserm since its creation. It has also showed the need to strengthen our country’s research over the long term to guarantee its sovereignty and international competitiveness.

Paris Saclay Cancer Cluster : une ambition mondiale pour l’oncologie française.

Posted on by Graziella Cara

Cancer Treatment: Identification of the Blood Vessels That Allow Killer Lymphocytes to Access and Destroy Tumors

Posted on by Graziella Cara

lymphocytes

Microscopic visualization of lymphocytes (in green) infiltrating a tumor HEV (in red) during combination anti-PD-1 plus anti-CTLA-4 immunotherapy. The white arrow indicates a lymphocyte that is leaving the bloodstream and entering the tumor (in black). © Elisabeth Bellard and Jean-Philippe Girard – IPBS (CNRS/UT3 Paul Sabatier)

Immunotherapy, a therapeutic strategy aimed at increasing the activity of the immune system in order to recognize and destroy cancer cells, has revolutionized cancer treatment over the past decade. A better understanding of how this therapeutic approach works, and more particularly how killer lymphocytes access tumors during immunotherapy, could improve the efficacy of the treatments. The team of Jean-Philippe Girard, Inserm Research Director at the Institute of Pharmacology and Structural Biology (French National Center for Scientific Research [CNRS]/Université Toulouse III – Paul Sabatier), in collaboration with Gustave Roussy, has recently discovered the essential role played in this process by specific blood vessels known as tumor-associated HEVs. For the first time, the scientists were able to film the lymphocytes infiltrating the walls of the HEV vessels to enter the tumors. What is more, the researchers have shown in animal models that increasing the proportion of HEV vessels in a tumor improves the efficacy of the immunotherapy and leads to the eradication of the tumors. Finally, they found that the likelihood of recovery of patients with metastatic melanoma (skin cancer) and treated with immunotherapy is increased when a large number of HEV vessels are present in tumors. The findings of this study have been published in the February 3, 2022 issue of Cancer Cell[1].   

Immunotherapy with therapeutic antibodies represents a real revolution in cancer treatment. In particular, it is used to cure certain patients with metastatic melanoma (skin cancer), who would previously not have survived. Unfortunately, immunotherapy is not effective in all patients or on all cancers. A better understanding of the mechanism of action of the treatment could improve it and make it effective in a larger number of patients. 

Killer lymphocytes – white cells present in the blood – are capable of eradicating cancer cells. It is essential that many of these killer cells have access to tumors in order to defend the body against cancer. The Toulouse team has lifted the veil on the mechanisms that allow killer lymphocytes to penetrate tumors in order to destroy them – either spontaneously or following immunotherapy with anti-PD-1 plus anti-CTLA-4 antibodies.

The scientists have discovered that the HEVs, very specific blood vessels known as high endothelial venules, constitute the major gateway of lymphocytes to tumors. Using sophisticated microscopy techniques, the researchers were able to film the passage of lymphocytes from the blood to the tumor in animal models. For the first time, they were able to visualize, directly and in real time, the lymphocytes in the process of infiltrating the walls of the HEV vessels in order to access the cancer cells in the tumor. “We thought that HEV vessels played an important role in the entry of lymphocytes into the tumor, but we were surprised to see that they were virtually the only gateway,” says Jean-Philippe Girard, Inserm Research Director and last author of the study.

The researchers then observed in their models that the presence of a large number of killer lymphocytes in tumors is associated with the presence of a large number of HEV vessels. What is more, they provided proof of concept that increasing the proportion of HEV vessels in a tumor improves the efficacy of combination anti-PD-1 plus anti-CTLA-4 immunotherapy and leads to tumor eradication.

Labeling of HEV vessels (brown) on a tumor section from a patient with metastatic melanoma and treated with immunotherapy. © Jean-Philippe Girard – IPBS (CNRS/UT3 Paul Sabatier)

Finally, in collaboration with Caroline Robert’s team at Gustave Roussy[2], the scientists studied patients with metastatic melanoma. They discovered that the presence of a large number of HEV vessels in tumors is associated with a better response to combination anti-PD-1 plus anti-CTLA-4 immunotherapy.

The next step for the researchers will be to develop treatments to increase the proportion of HEV vessels in tumors, in order to improve the efficacy of immunotherapy, allowing massive recruitment of killer lymphocytes to eradicate cancer cells.

“Our research could improve immunotherapy treatment in the longer term for patients with metastatic melanoma and other types of solid tumors. It also has prognostic implications, as clinicians can now look at the HEV vessels to predict a patient’s response to immunotherapy,“ concludes Girard.

 

[1] This study was funded by Fondation ARC, the Foundation for Medical Research (FRM), the French National Cancer Institute (INCa), the French National Research Agency (ANR), and Labex TOUCAN

[2] And also team leader at Inserm U981

COVID-19: A “Programmed Cell Death” Phenomenon in Hospitalized Patients

Posted on by Graziella Cara

Coronavirus SARS-CoV-2

SARS-CoV-2 coronavirus responsible for COVID-19 disease attached to human respiratory epithelial cells. ©M.Rosa-Calatraval/O.Terrier/A.Pizzorno/E.Errazuriz-Cerda

Almost 60% of patients hospitalized for COVID-19 have lymphopenia – a lower than normal number of lymphocytes[1] in the blood circulation. The mechanisms underlying this condition have long been poorly understood. In a new study, researchers from Inserm and Université de Paris[2] in collaboration with Canadian and Portuguese teams (Université Laval and Life and Health Sciences Research Institute [ICVS], respectively)[3] have revealed a phenomenon of programmed cell death known as “apoptosis”[4] that would explain the loss of lymphocytes in these patients. They have also shown in vitro that this process can be reversed by using caspase inhibitors – molecules that block the action of the enzymes responsible for apoptosis. These findings, published in the January 22, 2022 issue of Cell Death & Differentiation, make it possible to envisage new therapeutic avenues for patients with severe forms of COVID-19.

COVID-19 is a disease that varies broadly from one patient to another. While most infected people are asymptomatic or have mild symptoms, others develop severe forms of the disease.

Research on hospitalized patients had until now focused mainly on the inflammatory state that characterizes serious forms, and less so on other biomarkers. Yet among these patients, 60% have lymphopenia. The number of lymphocytes in their blood is lower than normal, especially the number of CD4 T cells.

lymphocytes apoptotiques

Detection of apoptotic lymphocytes with nuclear condensation and fragmentation visualizable by electron microscopy and not immunofluorescence. © Jérôme Estaquier

The team of Inserm researcher Jérôme Estaquier, at Unit 1124 (Inserm/Université de Paris) and Université Laval in Quebec, has studied this phenomenon. Thanks to their long history of researching AIDS – a disease for which a low blood CD4 level is a marker of poor prognosis – the scientists were able to apply their knowledge of these processes to COVID-19.

As part of their research, the scientists studied blood samples taken from patients hospitalized from April to June 2020 for COVID-19 (some of them in intensive care) and compared them with those of healthy donors. They showed that lymphopenia was correlated with the presence of several severity biomarkers, including the death ligand, FasL.

Programmed cell death  

They also showed that a process of programmed cell death – apoptosis – is responsible for the disappearance of CD4 T cells in hospitalized patients with COVID-19.

In an attempt to block this process, the researchers then drew on their previous HIV research in animal models, in which they had shown that administering molecules called caspase inhibitors can stop apoptosis, restore CD4 T cells, and prevent the onset of AIDS. Here they show that, with these molecules, the process of lymphocyte apoptosis is also reversible in the case of COVID-19.

These findings[5] open up new therapeutic avenues for the early treatment of hospitalized patients with lymphopenia. “The idea is now to set up phase 1 clinical trials to test the safety of caspase inhibitors in humans. CD4 cells are the cornerstone of the immune system. As such, these molecules could ultimately be useful for patients presenting with lymphopenia on admission to hospital, ” emphasizes Estaquier.

 

[1] Lymphocytes are white blood cells that play a key role in the immune system. They defend the body in the face of attacks.

[2] At Unit 1124 “Environmental Toxicity, Therapeutic Targets, Cellular Signaling and Biomarkers”

[3] The study was also conducted in collaboration with and the French National Center for Scientific Research (CNRS) (Institute of Human Genetics, IGH).

[4] Apoptosis is the programmed death of cells. This is a process by which cells trigger their self-destruction in response to a stress signal or death ligand.

[5] This study was funded by FRM and AbbVie. 

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