Inflammation and cancer: identifying the role of copper paves the way for new therapeutic applications

équipe CurieThe research team developed a “drug prototype” capable of mitigating both the mechanisms of inflammation and the processes potentially involved in metastatic spread. © Institut Curie / BELONCLE Frank

For the first time, researchers from Institut Curie, the CNRS and Inserm have uncovered a previously unknown chain of biochemical reactions. This chain involves copper and leads to metabolic and epigenetic alterations[1] that activate inflammation and tumorigenesis. But there is more; the research team developed a “drug prototype” capable of mitigating both the mechanisms of inflammation and the processes potentially involved in metastatic spread. Published in the journal Nature on April 26, 2023, these results provide hope for new therapeutic opportunities to control inflammation and cancer.

Inflammation is a complex biological process that can eradicate pathogens and promotes repair of damaged tissues. However, deregulation of the immune system can lead to uncontrolled inflammation and produce lesions instead. Inflammation is also involved in cancer. The molecular mechanisms underlying inflammation are not fully understood, and so developing new drugs represents a significant challenge.

As far back as 2020, Dr. Raphaël Rodriguez, CNRS research director and head of the Chemical Biology team at Institut Curie (Equipe Labellisé Ligue Contre le Cancer) at the Cellular and Chemical Biology laboratory (Institut Curie/CNRS/Inserm), had shed new light on a membrane receptor called CD44, which marks immune responses, inflammation and cancer progression. Dr. Rodriquez and his team showed that CD44 helped import iron into cell[2], triggering a series of reactions leading to activation of genes involved in the metastatic process.

“This is a cell plasticity phenomenon we continued to study, investigating other metals potentially internalized by CD44, notably copper,” he explains.


Copper causing epigenetic alterations

Along with his colleagues[3], Dr. Rodriguez has now reached a new milestone.

The research team managed to identify a signaling pathway involving copper and leading to the expression of pro-inflammatory genes in macrophages, the cells present in all tissues and playing an important role in innate immunity.

Once internalized in macrophages, copper enters into the mitochondria (the organelle responsible for cell respiration and energy production), where it catalyzes the oxidation of NADH into NAD+  (nicotinamide adenine dinucleotide, a molecule needed for the activity of certain enzymes). The increase of NAD+ in cells enables the activity of certain enzymes involved in the production of metabolites essential for epigenetic regulation. These metabolites thus, contribute to the activation of genes involved in inflammation.


Inflammation and cancer: shared molecular mechanisms

The scientists did not stop there, they also designed molecules able to bind to copper, inspired from the structure of metformin.[4] By testing these new molecules on models of acute inflammation, they found that a synthetic dimer of metformin, LCC-12 (also termed Supformin), reduced activation of macrophages and attenuated inflammation.

“Our work has enabled us to develop a drug prototype that inactivates copper chemistry in the cell’s metabolic machinery, thus blocking expression of the genes involved in inflammation”, explains Dr. Rodriguez.

To finish, they applied this therapeutic strategy to cancer cell models engaged in an epithelial-mesenchymal transition[5]. Here again, Supformin blocked the cellular mechanism and thus the cell transformation.

“The genes activated in cancer cells are not the same as those expressed in immune cells, but the chain reaction leading to epigenetic alterations is identical”, explains Dr. Rodriguez.

These results thus reveal the role of copper in cancer cells and their ability to adopt a metastatic nature.

Dr. Raphaël Rodriguez concludes: “Our study reveals that the inflammatory and cancer processes depend on similar molecular mechanisms and could therefore in the future benefit from similar innovative therapies, such as those tested with Supformin.”

The explanations of Dr. Raphaël Rodriguez in video :


[1]Epigenetics is the study of the mechanisms at play in gene regulation, which is essential to the action of cells and to maintaining their identity. Unlike genetic mutations, which are permanent, epigenetic modifications on DNA or histones are reversible.

[2] Read the press release “Cancer: a new mechanism that regulates cell activity involving iron”:

[3] This study was conducted at Institut Curie, in the Cellular and Chemical Biology unit (Institut Curie, CNRS, Inserm), in collaboration with UVSQ, Raymond Poincaré hospital (AP-HP), Gustave Roussy hospital, the Institut de chimie moléculaire et des matériaux d’Orsay (CNRS/University Paris-Saclay), the Multimodal Imaging Center (CNRS/Institut Curie/Inserm/University Paris-Saclay), the Center for Infection and Immunity of Lille (CNRS/Inserm/Institut Pasteur de Lille/CHU of Lille/University of Lille), Institute of Pharmacology and Structural Biology (CNRS/University of Toulouse III) along with British and Australian researchers.

[4]Metformin is a treatment used for Type-2 diabetes, and is able to form a bimolecular complex with copper.

[5] Epithelial-mesenchymal transition is the first step in enabling cancer cells to metastasize.

Cystic Fibrosis: A New Therapeutic Avenue Thanks to Research Into an Edible Mushroom

Lepista flaccida, champignon comestible

Lepista flaccida, an edible mushroom found in the northern hemisphere, was the focus of research by French teams into ways of correcting certain genetic mutations known as nonsense mutations. © MNHN/CNRS – Christine Bailly

A molecule obtained from an edible mushroom could open up therapeutic avenues for patients with cystic fibrosis, the most frequent rare genetic disease. A team led by Fabrice Lejeune, Inserm researcher at the Cancer Heterogeneity, Plasticity and Resistance to Therapies laboratory[1] (Inserm/ CNRS/ Université de Lille/Institut Pasteur de Lille/University Hospital Lille) tested the effects of 2,6-diaminopurine (DAP), one of the active principles contained in the Lepista flaccida mushroom, in different experimental models of the disease.  The scientists have shown that this molecule could be of therapeutic value in patients with cystic fibrosis linked to a particular type of mutation known as a nonsense mutation. Their findings have been published in Molecular Therapy.

Around 6,000 people in France have cystic fibrosis, a genetic disease that primarily affects digestive and respiratory function, and has a 40 to 50-year life expectancy. Nevertheless, therapeutic innovations have improved patient prognosis in recent years. Treatments are now available for the vast majority of patients – those whose disease is caused by the delta F508 mutation of the CFTR gene. In these patients, the CFTR protein (coded by the CFTR gene) is present in small amounts but is dysfunctional. The molecules currently available are able to correct this dysfunction and significantly improve their clinical symptoms.

However, they are not effective in the 10% of patients for whom the protein is completely absent, as is the case when the disease is linked to a nonsense mutation (see box).

Nonsense Mutations and Genetic Diseases

DNA is made up of nucleotides, organic compounds that code the amino acids implicated in the synthesis of the proteins needed for the body to function correctly. In practice, nonsense mutations introduce a “stop codon” in the mutated gene, i.e. a sequence of nucleotides that brings the synthesis of the corresponding protein to a premature halt. From that point, the protein is no longer produced, leading to the onset of the clinical symptoms of the disease.

Identifying ways to correct nonsense mutations is therefore an important challenge for researchers studying genetic diseases and who hope to develop new therapeutic options against cystic fibrosis.

In this context, Inserm researcher Fabrice Lejeune and his team[2] made an innovative finding in 2017 by showing that extracts of a commonplace edible mushroom known as Lepista flaccida could repair nonsense mutations in three cell lines isolated from cystic fibrosis patients. A few years later in 2020, Lejeune and his team published a study identifying the active principle in the mushroom that is capable of correcting the nonsense mutations associated with the UGA stop codon – the most common of the three stop codons of the human genetic code. The active principle concerned was 2,6 diaminopurine (DAP).

In their latest research, the scientists tested the effects of this molecule in four experimental models of cystic fibrosis: animal models of the disease, developed in the laboratory; cell lines; patient cells and organoids. This diversity of models makes it possible to be as close as possible to what is happening in the patient’s body, in order to assess the potential therapeutic benefits they may obtain.

The results obtained by the team suggest that DAP corrects the nonsense mutation in the different models studied, by re-establishing protein production and effectively restoring the function of the mutated gene.

In clinical terms, this results in an improvement in symptoms in animals. The treatment with DAP makes it possible to restore CFTR expression in the lungs and intestines as well as the function of this protein, significantly reducing the premature mortality observed prior to administration of this molecule.

In addition, the research team has also shown that DAP can be given orally and that it is distributed effectively throughout the body for around two hours. These characteristics are also a positive point when it comes to considering DAP as a serious therapeutic avenue, as this means that we could reach all the tissues in the body while limiting the duration of exposure to the molecule, thereby reducing possible side effects.

“DAP could represent the first molecule capable of providing therapeutic benefit to patients with cystic fibrosis linked to a nonsense mutation and, more broadly, to patients with a genetic disease linked to a nonsense mutation,” explains Lejeune.

These results pave the way for a potential clinical trial in the coming years to test the efficacy of the molecule in patients. Before this, the goal is to develop the best possible formulation for the drug and to carry out toxicity tests to ensure its safety in humans. In the shorter term, the teams also want to test DAP in models of other rare genetic diseases, particularly Duchenne muscular dystrophy and Rett’s syndrome, for which over 60% of patients are affected by nonsense mutations.


[1] Cancer Heterogeneity, Plasticity and Resistance to Therapies laboratory at the ONCOLille institute

[2]The following research units also contributed to these findings: Communication Molecules and Adaptation of Micro-organisms (CNRS/MNHN), Biometrics and Evolutional Biology Laboratory (CNRS/Université Claude Bernard Lyon 1/VetAgro Sup), Lille Platforms in Biology and Health (PLBS) (CNRS/University Hospital Lille/Inserm/Institut Pasteur Lille/Université Lille), Strasbourg Platform for Integrative Biological Chemistry (CNRS/Université de Strasbourg).

A potential therapy to reduce the side effects of a chemotherapy

Convergent effect of cisplatin and KW6002 on DNA double-strand breaks in lung tumor cells. Blue corresponds to cell nuclei and red to a protein that marks DNA damage © Dewaeles et al

Cisplatin is a chemotherapy indicated to fight tumors in many types of cancer. However, it does have major side effects – especially kidney toxicity, that can lead to acute kidney failure. In addition, patients treated with cisplatin also often report high levels of neuropathic pain. Scientists from Inserm, Université de Lille, University Hospital Lille, CNRS and Institut Pasteur de Lille within the CANTHER and Lille Neuroscience & Cognition laboratories, in collaboration with researchers from Michigan State University (USA), have identified a drug that could be a game changer for patients. Istradefylline, which is already approved for Parkinson’s disease, could not only reduce the harmful effects of cisplatin but also improve its anti-tumor properties. These findings will now need to be confirmed in a clinical trial. The study is published in The Journal of Clinical Investigation.

Cisplatin is a chemotherapy used to treat several types of cancer, in particular lung, ovarian and testicular cancers. While its anti-tumor efficacy has been proven, cisplatin promotes side effects. These include intense pain (peripheral neuropathy) and kidney damage, leading to acute kidney failure in one third of cases. Currently, there is no effective solutions to limit side effects for patients exposed to cisplatin.

An international work conducted by Christelle Cauffiez, David Blum and Geoffroy Laumet[1] have now identified a molecule that reduces cisplatin-induced side effects, while preserving or even potentiating its anti-tumor properties.


A Parkinson’s disease drug

The scientists focused on a drug called istradefylline, which is already approved in the USA and Japan for the treatment of Parkinson’s disease. Biologically, this compound blocks the adenosine receptors receptors at the surface of cells.

Blum’s team, which is working on neurodegenerative diseases, had previously observed an increased density of these receptors in the brains of patients with dementia, a phenomenon involved in the development of these diseases. Interestingly, a comparable increase of adenosine receptors was also observed by Cauffiez’s team in the kidneys, under exposure to cisplatin.

With this in mind, the scientists decided to join forces with Laumet’s lab, a specialist of  cisplatin-induced neuropathic pain, to test the impact of istradefylline to mitigate the harmful effects of cisplatin.


Findings to confirm in a clinical trial

Their experiments, conducted on animal and cellular models, indeed pointed towards a beneficial role of istradefylline. In mice exposed to cisplatin, the molecule not only reduced kidney damages but also prevented neuropathic pain.

In addition, cisplatin’s ability to reduce tumor growth was increased in the animals receiving istradefylline – an effect subsequently confirmed in cell models.

Before considering the widespread application of this therapeutic approach to patients with cancer, these findings must however first be consolidated by organizing a rigorous clinical trial. The fact that istradefylline is already used in humans to treat another disease already constitutes an interesting perspective.

“In fact, we already have a lot of clinical data showing that this molecule is safe. While it is necessary to conduct a clinical study to test its efficacy in reducing the side effects of the chemotherapy, the possibility of therapeutic repositioning is a promising perspective for improving patient care in the short term,” the researchers point out.


[1] from the CANTHER laboratory (Inserm/Institut Pasteur de Lille/CNRS/Université de Lille/University Hospital Lille), the Lille Neuroscience & Cognition laboratory (Inserm/Université de Lille/University Hospital Lille) and the Department of Physiology of Michigan State University

Infertility: New Avenues to Understand the Harmful Effects of Chemotherapy

Immunostaining of a mouse testicle section

Immunostaining of a mouse testicle section, with (in red) the undifferentiated germ cells and (in green) the GFP protein reflecting TGR5 receptor expression in this study model. ©David Volle/Inserm

Infertility is a public health problem affecting millions of couples in France. Among the possible causes, chemotherapy has been singled out as having particularly harmful effects on the fertility of both women and men. In order to better prevent and restore fertility in cancer survivors, understanding the mechanisms behind these negative effects is a priority. In a new study, researchers from Inserm, CNRS and Université Clermont Auvergne investigated a receptor found on male germ cells that produce gametes, their aim being to find out more about its role in chemotherapy-related infertility. Their findings, published in Advanced Science, pave the way for a better understanding of male infertility and the development of treatments to reduce the risk of sterility from chemotherapy.

Around 3.3 million people in France are directly affected by infertility. Concerning both men and women, it has continued to increase in recent years, making it a major public health problem [1].

While there are many causes of infertility, it is currently well established that cancer treatments, including chemotherapy, can have particularly harmful effects on male and female fertility. Although cancer therapies have improved in recent years, tackling this issue is becoming a matter of urgency, as an increasing number of cancer survivors will be affected by infertility problems.

For almost 15 years, Inserm researcher David Volle and his team at the Genetics, Reproduction and Development Laboratory (Inserm/CNRS/Université Clermont Auvergne) have sought to improve their understanding of the biological mechanisms underlying infertility. Part of their research focuses on the impact of chemotherapy on male fertility, with the longer-term objective of identifying avenues to counter the adverse effects of this treatment.

In their new study, the researchers looked at TGR5 receptors, which are present on cell membranes, in order to understand their role in the harmful effects of chemotherapy.

TGR5 receptors are widely studied in the context of metabolic diseases, such as diabetes and obesity. They are activated by bile acids – molecules produced in the liver that regulate certain physiological functions, including blood glucose and energy expenditure.

 However, previous research by the team had shown that these receptors are also present in germ cells, the cells that produce gametes. In mouse models mimicking liver disease, with elevated bile acid levels, the scientists had found that the TGR5 receptors on germ cells were activated – which was associated with increased sterility in animals.

Germ cell death

To further understand the impact of TGR5 on fertility in the context of chemotherapy, the scientists in their latest study exposed mice to a chemotherapy agent called busulfan. They then showed that the chemotherapy induces the death of some of the germ cells in healthy mice, thereby affecting their fertility. “The fact that it is the germ cells, at that point undifferentiated, which are affected is particularly problematic because we are talking about the reserve of cells that produce gametes. This can reduce their renewal and contribute to post-chemotherapy infertility,” says Volle.

However, in mice that have been genetically modified to have an absence of TGR5 receptors, the effects of chemotherapy on germ cells are attenuated. This results in an accelerated return of fertility in these busulfan-treated mice compared with the control mice.

Our study has therefore improved our understanding of the molecular mechanisms involved in the harmful effects of chemotherapies on germ cells and fertility. These findings show that TGR5 receptors play an important role in the harmful effects of chemotherapy on infertility,” adds Volle.

In the longer term, the objective is to develop methods to modulate TGR5 receptor activation in a targeted manner within germ cells, in order to protect them and restore fertility after chemotherapy.

The idea is also to assess whether these data can be extrapolated to other disease contexts in which TGR5 receptor activity could be modulated, such as obesity and diabetes, conditions known to impair fertility.

In addition, in parallel to this research, the team observed that even when fertility was maintained in mice exposed to chemotherapy, the quality of the gametes was affected. The scientists will therefore now endeavor to understand both the quantitative and qualitative impacts on germ cells in order to limit not just fertility disorders but also the longer-term consequences on the offspring of animals.


[1] A report requested by the French Minister of Health and the Secretary of State for Childhood and Family in February 2022 outlines a national strategy to combat infertility: https://solidarites-

Colon cancer: how mutation of the APC gene disrupts lymphocyte migration

Migrating human T lymphocytes

In patients with familial adenomatous polyposis, a genetic disease predisposing to colon cancer, mutations of the APC gene induce the formation of intestinal polyps, but also reduce immune system activity. In a new study, researchers from the Institut Pasteur, INSERM(1) and Université Paris Cité describe the mechanisms that modify the structure of T lymphocytes and hinder their migration towards the tumors to be destroyed. This discovery, published in the journal Science Advances on April 13, 2022, provides new perspectives on the migration of immune cells, a key process in antitumor immune defense.

As its name suggests, familial adenomatous polyposis is transmitted from generation to generation. The cause: mutations of the tumor suppressor gene APC (adenomatous polyposis coli). People who inherit these mutations develop hundreds, possibly thousands, of polyps in their colon from adolescence, then colorectal cancer(2) in adulthood if the polyps are not surgically removed. “As it’s a hereditary disease, all of the body’s cells carry the mutation and can be affected in different ways”, explains Andrés Alcover, Head of the Lymphocyte Cell Biology Unit at the Institut Pasteur and joint senior author of the study. “Today we know that these mutations disrupt the functioning of colon cells but also cells of the immune system”.

In previous studies, the team of researchers from the Institut Pasteur, CNRS and Inserm – funded by the French Cancer League since 2018(3) – demonstrated the dual impact of APC mutations.

Not only do these mutations prevent intestinal epithelial cells from differentiating correctly and cause them to form tissue growths (polyps), they also adversely affect the functioning of immune cells, thereby preventing them from effectively combating polyps and tumors. Two mechanisms that together promote the growth of tumors.

In order to better understand what prevents immune cells from fulfilling their role, the researchers this time decided to take a closer look at the T lymphocytes whose mission is to detect and destroy tumors by infiltrating them. To this end, biologists and clinical research physicians of the Institut Pasteur’s ICAReB platform, Dr. Hélène Laude and Dr. Marie-Noëlle Ungeheuer, approached the patient association POLYPOSES FAMILIALES France. A new clinical research project involving the association recruited patient volunteers for the collection of blood samples. “Thanks to the association, we met patients and also clinicians specialized in polyposis. We learned a lot about this complex pathological condition, the experience of patients and families, and the different levels of disease severity. We recognize the valuable role of the patients, who were highly motivated to take part in the study, and the input of specialists”, pointed out Andrés Alcover.

The naturally mutated T lymphocytes present in the blood of these patients were cultured then subjected to several in vitro experiments. Using several microdevices – filters, channels, protein substrates and layers of vascular endothelial cells – the researchers could compare the behavior of diseased lymphocytes with that of lymphocytes from healthy volunteers.

They studied how lymphocytes moved along biological surfaces similar to blood vessel walls, but also how easily they could separate cells and cross tightly packed cell layers.

“In order to move along blood vessel walls, cross them and reach the tumor to be infiltrated, healthy lymphocytes change their morphology. Something akin to a large adhesive foot, supported by the lymphocyte’s cytoskeleton, grows longer in the direction of migration. This polarization is essential for movement in the right direction,” explains Marta Mastrogiovanni, researcher in the Institut Pasteur’s Lymphocyte Cell Biology Unit and lead author of the study. In mutated lymphocytes, the microtubules making up the cytoskeleton are disorganized and there are fewer adhesion proteins. The cells lose their polarity and their ‘muscles'”.

Although the mutated T lymphocytes are not necessarily moving more slowly than healthy lymphocytes, they adhere less well to the walls and have more difficulty moving in a given direction and passing through the walls. In short, this research showed their migration to be less effective. “This discovery is important because the motility of immune cells is a key process in antitumor immune defense. “We know that the immune system is very important in combating pathogens but we sometimes forget that it also contributes to combating cancer cells”, concludes Vincenzo Di Bartolo, researcher in the Institut Pasteur’s Lymphocyte Cell Biology Unit and joint senior author of the study.


(1) Collaborative project: Institut Pasteur, Department of Immunology and  and Center for Translational Science (CRT, ICAReB), and Institut Pasteur, Institut Cochin, Institut Curie, and Institut Pierre-Gilles de Gennes.

(2) Familial adenomatous polyposis accounts for 1% of all colorectal cancers. 

(3) Funding via the French Cancer League (La Ligue Contre Le Cancer), 2018-2022 “Équipe Labellisée” program, the Institut Pasteur and Inserm. Marta Mastrogiovanni was funded by the Pasteur-Paris University International Doctoral Program and the European Union Horizon 2020 Research and Innovation Programme under Marie Sklodowska-Curie grant agreement 665807 and La Ligue Contre Le Cancer, doctoral grant 4th year of PhD.

Artificial Sweeteners: Possible Link to Increased Cancer Risk

édulcorant artificiel

Aspartame, a well-known artificial sweetener, is for example present in thousands of food products worldwide. © Mathilde Touvier/Inserm

Artificial sweeteners are used to reduce the amounts of added sugar in foods and beverages, thereby maintaining sweetness without the extra calories. These products, such as diet sodas, yoghurts and sweetener tablets for drinks, are consumed by millions of people daily. However, the safety of these additives is the subject of debate. In order to evaluate the risk of cancer linked to them, researchers from Inserm, INRAE, Université Sorbonne Paris Nord and Cnam, as part of the Nutritional Epidemiology Research Team (EREN), analyzed data relating to the health of 102,865 French adults participating in the NutriNet-Santé cohort study and their consumption of artificial sweeteners. The results of these statistical analyses suggest a link between the consumption of artificial sweeteners and an increased risk of cancer. They have been published in PLOS Medicine.

Given the adverse health effects of consuming too much sugar (weight gain, cardiometabolic disorders, dental caries, etc.), the World Health Organization (WHO) recommends limiting free sugars1 to less than 10% of one’s daily energy intake2. Therefore, in order to ensure that foods maintain that sweet taste so sought after by consumers worldwide, the food industry is making increasing use of artificial sweeteners. These are additives that reduce the amount of added sugar (and calories) without reducing sweetness. What is more, in order to enhance flavor, manufacturers use them in certain products that traditionally contain no added sugar (such as flavored potato chips).

Aspartame, a well-known artificial sweetener, is for example present in thousands of food products worldwide. While its energy value is similar to that of sugar (4 kcal/g), its sweetening power is 200 times higher, meaning that a much smaller amount is needed to achieve a comparable taste. Other artificial sweeteners, such as acesulfame-K and sucralose, contain no calories at all and are respectively 200 and 600 times sweeter than sucrose.

Although several experimental studies have pointed to the carcinogenicity of certain food additives, there are no robust epidemiological data supporting a causal link between the everyday consumption of artificial sweeteners and the development of various diseases. In a new study, researchers sought to examine the links between the consumption of artificial sweeteners (total and most often consumed) and the risk of cancer (global and according to the most common types of cancer) in a vast population study. They used the data provided by 102,865 adults participating in the NutriNet-Santé study (see box below), an online cohort initiated in 2009 by the Nutritional Epidemiology Research Team (EREN) (Inserm/Université Paris Nord/CNAM/INRAE), which also coordinated this work.

The volunteers reported their medical history, sociodemographic data and physical activity, as well as information on their lifestyle and health. They also gave details of their food consumption by sending the scientists full records of what they consumed over several 24-hour periods, including the names and brands of the products. This made it possible to accurately evaluate the participants’ exposure to additives, and more particularly to artificial sweeteners.

After collecting information on cancer diagnoses over the NutriNet-Santé study period so far (2009-2021), the researchers conducted statistical analyses in order to study the links between the use of artificial sweeteners and the risk of cancer. They also took into account various potentially confounding factors, such as age, sex, education, physical activity, smoking, body mass index, height, weight gain over the study period so far, family history of cancer, as well as intakes of energy, alcohol, sodium, saturated fatty acids, fiber, sugar, whole grain foods and dairy products.

The scientists found that compared with those who did not consume artificial sweeteners, those who consumed the largest amounts of them, especially aspartame and acesulfame-K, were at increased risk of developing cancer, irrespective of the type.

Higher risks were observed for breast cancer and obesity-related cancers.

In accordance with several in vivo and in vitro experimental studies, this large-scale, prospective study suggests that artificial sweeteners, used in many foods and beverages in France and throughout the world, may represent an increased risk factor for cancer,” explains Charlotte Debras, PhD student and lead author of the study. Further research in other large-scale cohorts will be needed in order to replicate and confirm these findings.

These findings do not support the use of artificial sweeteners as safe alternatives to sugar, and they provide new information in response to the controversy regarding their potential adverse health effects. They also provide important data for their ongoing re-evaluation by the European Food Safety Authority (EFSA) and other public health agencies worldwide,” concludes Dr. Mathilde Touvier, Inserm Research Director and study coordinator.

NutriNet-Santé is a public health study coordinated by the Nutritional Epidemiology Research Team (EREN, Inserm / INRAE / Cnam / Université Sorbonne Paris Nord) which, thanks to the commitment and loyalty of over 170,000 participants (known as “Nutrinautes”), advances research into the links between nutrition (diet, physical activity, nutritional status) and health. Launched in 2009, the study has already given rise to over 200 international scientific publications. In France, new participants are currently being encouraged to join in order to continue to advance research on the relationship between nutrition and health.

By devoting a few minutes per month to answering various online questionnaires relating to diet, physical activity and health, participants contribute to furthering knowledge of the links between diet and health. With this civic gesture, we can each easily participate in research and, in just a few clicks, play a major role in improving the health of all and the wellbeing of future generations. These questionnaires can be found on the secure platform


1 Sugars added to foods and beverages and sugars naturally present in honey, syrups, and fruit juices.

2 World Health Organization, 2015

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

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.

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

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

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

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


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