A Potential New Strategy for Treating Tumors

Coupe transversale d'un mélanome

Coupe transversale d’un mélanome avec les MTA CD163 (macrophages associés aux tumeurs) colorés en vert, les vaisseaux sanguins colorés en rouge et le noyau des cellules coloré en gris. © 2019 Etzerodt et al.

An international team led by Toby Lawrence, Inserm researcher at Unit 1104 Center of Immunology Marseille-Luminy (Inserm / CNRS / Aix-Marseille Université), has developed a potential therapy to reduce tumor size, where previous drugs have failed. Its findings have been published in Journal of Experimental Medicine.

Tumors develop from abnormal cells in the body that continue to grow, forming lumps. While these can be benign, they can also become malignant and lead to cancer.

Malignant tumors, infiltrated by immune cells known as macrophages, usually help the body’s immune defenses. But tumor-associated macrophages (TAMs) are manipulated by cancer cells to not only contribute to the growth and spread of tumors in the body, but also to the suppression of our natural immune defenses against them.

It was in order to counteract this dual mechanism in the growth and spread of tumors that an international team including researchers from Inserm and King’s College London have designed a therapy that targets TAMs without suppressing other macrophages. In a study published in Journal of Experimental Medicine, the researchers explain how they were able to target the “bad” TAMs without suppressing the body’s own natural defenses.

Other recent developments in cancer therapy include drugs known as immune checkpoint inhibitors (ICIs) which have revolutionized the field, especially for melanoma patients. However, patients who do respond to ICI therapy experience severe side effects and over 70% of patients do not respond at all.

In this study, the authors used mouse models of melanoma resistant to ICI therapy.

They were able to specifically target the “bad” TAMs, responsible for massive immune cell recruitment, and significantly reduce tumor size.

According to Toby Lawrence, the Inserm researcher who led the study, this research could lead to the creation of a drug to specifically kill TAMs.

“We were astounded to see how effective targeting a specific subset of TAMs was in reducing tumor growth in this model, where ICI therapy had no impact, he states. This study not only provides a new strategy for targeting specific TAM subsets in the clinic, but also shows why it’s important to target specific TAM subsets and not other macrophages that help anti-tumor immune responses.”

Post-menopause Treatment: Persistent Excess Risk of Breast Cancer

It has been known for about ten years that some oestrogen/progestin menopausal hormone therapies (MHT) are associated with an increased risk of breast cancer. Studies have nonetheless suggested that this risk is rapidly attenuated or even eliminated in 2-5 years if the patients stop their treatment. However, questions remain regarding this attenuation, and its relationship to the initial duration of treatment and with the types of drugs administered. The Inserm “Nutrition, Hormones and Women’s Health team at the Centre for Research in Epidemiology and Population Health (U1018, CESP, Villejuif) has studied these questions using data from the E3N cohort.

Cancer sein Fournier

© Fotolia

In a study published last April, the researchers succeeded in showing that women given MHT remain at higher risk of getting breast cancer several years after finishing their treatment compared with women who have never had MHT.

This risk would apply only to women who have been treated for a long period, i.e. longer than 5 years, with a combined MHT that includes oestrogen and a progestin other than micronised progesterone or dydrogesterone.

“Our study shows that if the risk of getting breast cancer is twice as high for women at the time of treatment, it remains 1.4 times as high in the 5 years following interruption of treatment, and for 5-10 years after. After 10 years following cessation, the risk remained higher for women who had been treated, but the results were based on insufficient numbers and insufficient statistical significance,” explains Agnès Fournier.

The team concludes this study by saying that “additional studies are needed,” to find out exactly how long this excess risk persists over time.

Since its beginnings in 1990, the E3N cohort study has received sustained support from the French National Cancer League and its departmental committees. Besides the League, the other three founding partners are Inserm, Gustave Roussy Institute and MGEN (mutual insurance company). IReSP (French Public Health Research Institute) helped to fund the present project.

A major advance in colon cancer

A French consortium of clinicians and biologists has proposed a molecular classification of colon cancers into six sub-types. 

A national multicentric consortium of clinicians, biologists and researchers performed a genomic study as part of the CIT programme (Cartes d’Identité des Tumeurs® [Tumour Identity Cards]) of the Ligue contre le Cancer. The study included tumours from 566 patients suffering from colon cancer, the results of which were published in the international journal PLOS MEDECINE.

In analysing a transcriptome of this cohort that is perfectly described clinically and pathologically, the consortium produced a robust classification into six molecular sub-types that were well-defined in terms of changes to the genome and signalling routes associated with a gene expression signature.

These six sub-types are correlated to separate prognoses. The classification was validated using an independent series of 1,181 colon cancers.

It is planned to apply the signature of each sub-type to other series of colon tumours  with the aim of obtaining a routinely transferable diagnostic tool so as to improve the prognosis and to guide treatment.

Épithélium du côlon

crédit : ©Inserm

Genetic mutation and the prognosis for renal polycystosis

The team headed by Claude Férec, director of INSERM 1078 “Genetics, functional genomics and biotechnologies” (INSERM/Université de Bretagne/EFS) in Brest, published results in the Journal of the American Society of Nephrology from a cohort of 700 patients suffering from Autosomal Dominant Polycystic Kidney Disease (ADPKD). This condition, the most frequent monogenetic hereditary kidney disease, manifests through the slow and progressive appearance of cysts, mainly on the kidneys.

Researchers showed from the Genkyst cohort that the type of mutation that affects the genes in question in the manifestation of the illness is strongly associated with kidney survival. The median age for terminal renal failure in the illness is 12.3 years earlier when it involves a deleterious mutation in the PKD1 gene, i.e. when all or part of the protein is missing. This type of mutation disrupts the gene’s ability to read which it needs for the long process terminating in the synthesis of proteins. The average age of patients who have reached the terminal renal stage is thus 55.6 years compared to 67.9 years for those not presenting with this type of mutation and 79 years for those with the mutation in the PKD2 gene.

A complete molecular analysis of the PKD1 and PKD2 genes in question enabled Claude Férec’s team, in the context of a project implemented in collaboration with the team headed by Yannick Le Meur, to identify a mutation in 93% of the patients in the cohort.

“Genkyst makes it possible to better establish a relationship between patients’ genotype and phenotype and shows for the first time that the genetic mutation in this illness has a major impact on the way renal function alters over time,”

 concludes Claude Férec, principal author of the study.

A mother’s exposure to atmospheric pollution results in a risk of her baby having low birth weight

© AdobeStock

An international study coordinated by Professor Tracey Woodruff of the University of San Francisco reveals that mothers exposed to atmospheric pollution due to particles in suspension in the air (vehicle emissions, city central heating systems and coal-burning power stations) presented with a higher risk of bearing babies with a low birth weight. This study, of which the French section was assigned to Rémy Slama and Johanna Lepeule, researchers at the INSERM U823 Unit, the Centre de recherche Institut Albert Bonniot, was published on 6 February 2013 in the journal entitled Environmental Health Perspectives.

The study involved an analysis of data collected from three million births recorded in North America, South America, Europe, Asia andAustralia. The study was based on registers of births (recorded electronically and easily accessible in certain countries) and epidemiological cohorts. InFrance, the women and children who took part were from theEdencohort, coordinated by INSERM inNancyandPoitiers.

The researchers established, from various sites throughout the world, that the higher the level of pollution, the greater the proportion of seriously underweight births. The findings are consistent with results previously obtained by the INSERM environmental epidemiology team headed by Remy Slama:

using the Eden cohort as the basis, for which we recovered the fœtus scans, we noted that atmospheric pollution appeared to restrict fœtus growth from the mid-term of pregnancy”.

A low birth weight (a weight of less than 2,500 kg) implies serious health consequences, including greater risk of morbidity and post-natal mortality, as well as chronic health problems later in life”, notes the main author Payam Dadvand, MD, PhD, of the Centre pour la recherche en épidemiologie environnementale (CREAL) in Barcelona, Spain.

The important element observed is that the risks emerge at atmospheric pollution levels to which virtually the whole world population is regularly exposed”, explains Tracey J. Woodruff.

The INSERM team, headed by Remy Slama in Grenoble, is currently coordinating an analysis based more specifically on new-borns in ten European countries (as part of the ESCAPE project) that is designed to confirm whether these effects on birth rate have been observed on a Europe-wide scale and to define more specifically the role of urban pollutants.

The question of the effects of such exposure post-natally is currently being examined through epidemiological monitoring of certain children participating in the study.

Particulate pollution is measured by concentration (in micrograms per cubic metre) of particles that are sufficiently fine to be able to penetrate deeply into the lungs. In theUnited States, the regulations require the average annual atmospheric concentration not to exceed 12 µg per cu. m. of particles measuring less than 2.5 microns (or PM2.5). The European limit has been fixed at 25 µg per cu.m. and the European Union’s regulating agencies are currently examining the possibility of reducing this threshold. This limit is not complied with in certain metropolises, especially at sites close to heavy road traffic. The World Health Organization’s target value of 10 µg per cu. m. is not met in a large number of French metropolises.

Regulatory T cells, ensuring a good immune memory

Regulatory T cells (Treg) are a sub-population of immune cells that prevent each individual from triggering immune reactions against his/her own organs.  In the context of some illnesses, these mechanisms may be defective: in this case, the term “auto-immune reactions” is applied. In this new research, published in the Science review, the team of researchers directed by Sebastian Amigorena (Institut Curie / Inserm U932 Immunity and Cancer unit) demonstrates that the regulatory T cells are also important during immune responses to external antigens, i.e. during infection.

By regulating the interactions between cells with antigens and T cells, Treg prefer engaging “high affinity” cells in terms of antigens, thus boosting the immune response. However, if there are no Treg, this first stage of immune response is defective, leading – in time – to an incorrect memorization process of pathogens and, consequently, to reduced defense mechanisms against infection (for example).

Shedding light on this new property of regulating T cells could prove significant in terms of developing vaccination strategies over time.

crédit photo M Depardieu/Inserm

Excess body weight: a risk factor for a second cancer

Excess body weight (overweight and obesity) currently concerns nearly one in two French adults. It is associated with an increased risk of several primary cancers, including postmenopausal breast cancer.

Researchers at an Inra-Inserm-Cnam-Université Paris 13 joint research unit, part of NACRe(1), worked with a team from Imperial College London to carry out the first systematic review and meta-analysis of the results of prospective studies on the relationship between excess body weight and the risk of second cancers following breast cancer.

Their results show that obesity at diagnosis of a first breast cancer increases the risk of developing a second cancer in the same or other breast, in the endometrium or the colon/rectum. The results stress the importance of implementing preventive measures to reduce the prevalence of overweight and obesity.

(1) NACRe (the French food and cancer research network)


© Inserm/T.Depardieu via Serimedis.

Infertility treatments and retinoblastoma: a low risk

Retinoblastoma is the most common eye tumor in children, with an occurrence rate of one for every 15 to 20,000 births. Even today, little is known about the risk factors for this cancer. Recent studies have suggested an increased risk of retinoblastoma in children conceived using in vitro fertilization (IVF), but these results were contradicted by other research studies.

Researchers from Inserm unit 953 (Epidemiologic research into perinatal health and the health of women and children), in collaboration with the Institut Curie and the Research Centre into epidemiology and population health (CESP), have just published the results of the EPIRETINO study into the risk of retinoblastoma associated with infertility treatments (IVF, ovarian stimulation or intrauterine insemination); the results were published in the Human Reproduction review.

The results obtained from 244 non-hereditary forms of retinoblastoma compared with 28,170 births (representative of French births) did not demonstrate an increased risk of retinoblastoma. However, high maternal ages and hypofertility (with two-year periods taken to conceive) are risk factors for retinoblastoma.