3D structure of a melanoma cell derived by ion abrasion scanning electron microscopy. Credit: Sriram Subramaniam/ National Cancer Institute
Vitamin D has many effects on the body, including regulation of the immune system. New research indicates that for patients with advanced skin cancer, it may be important to maintain normal vitamin D levels when receiving immunotherapy in the form of immune checkpoint inhibitors. The findings are published in CANCER.
To see whether levels of vitamin D might impact the effectiveness of immune checkpoint inhibitors, investigators analysed the blood of 200 patients with advanced melanoma both before and every 12 weeks during immunotherapy treatment.
A favourable response rate to immune checkpoint inhibitors was observed in 56.0% of patients in the group with normal baseline vitamin D levels or normal levels obtained with vitamin D supplementation, compared with 36.2% in the group with low vitamin D levels without supplementation. Progression‐free survival in these groups was 11.25 and 5.75 months, respectively.
“Of course, vitamin D is not itself an anti-cancer drug, but its normal serum level is needed for the proper functioning of the immune system, including the response that anti-cancer drugs like immune checkpoint inhibitors affect,” said lead author Łukasz Galus, MD, of Poznan University of Medical Sciences, in Poland. “In our opinion, after appropriately randomised confirmation of our results, the assessment of vitamin D levels and its supplementation could be considered in the management of melanoma.”
Scanning electron micrograph of a macrophage. Credit: NIAID
Cell proliferation from stem cells is vital for organisms to grow and form vital organs. In cancer, however, cell proliferation is no longer controlled and becomes chaotic. Research published in Nature Immunology revealed that monocytes, which are blood immune cells previously thought to be already differentiated, can in fact still proliferate. The study’s researchers at the University of Liège have discovered that, in a healthy individual, monocytes also have this ability to proliferate, in order to replace tissue macrophages.
Monocytes are white blood cells that derive from the bone marrow. A monocyte is part of the innate immune response and functions to regulate cellular homeostasis, especially in the setting of infection and inflammation. They account for approximately 5% of circulating nucleated cells in normal adult blood.
The formation of complex multicellular organisms necessitates billions of cells to be produced from progenitor cells, proliferating and taking on particular morphologies and functions while assembling into tissues and organs. Most of the cells that constitute a living organism are understood to arise from stem cells. When they stop proliferating, they specialise, differentiate and form muscles, brain, bones, immune cells, etc. When proliferation is no longer properly regulated, this can lead to the development of various diseases, chief if which is cancer.
Professor Thomas Marichal (Professor at ULiège, Welbio investigator at the WEL Research Institute) and his team from the GIGA Institute at ULiège discovered that this ability to proliferate is not merely restricted to stem cells, but is also an as-yet-unknown function of blood immune cells, the monocytes.
Indeed, blood monocytes, previously considered as differentiated cells, are capable of proliferating and generating a pool of monocytes in the tissues in order to give rise to macrophages, which are important immune cells that protect us against microbes and support the proper functioning of our organs.
“This is a major fundamental discovery, which changes our conception of the involvement of cell proliferation in the constitution and maintenance of our immune system,” explains Thomas Marichal, director of the study. “Our finding also suggests that the information that can be drawn from an enumeration of blood monocytes, classically carried out during a blood test, would reflect only little of what is happening at the level of the tissues, during ‘infection or inflammation, for example, since monocytes can proliferate when they enter tissues.”
He also adds, “Fortunately, this proliferation is extremely well controlled and does not lead to a humoral process. It has only one goal: to allow, as effectively as possible, the replacement of immune cells that populate our tissues: the macrophages.”
This discovery was possible thanks to the development of new tools and the use of innovative technologies. “This study is a great example of how technological advances can drive breakthrough scientific discoveries. It would have been extremely difficult, if not impossible, to study with such a resolution this population of proliferating monocytes only 10 years ago. This required the use of state-of-the-art equipment recently acquired at the GIGA Institute, the generation of complex genomic data and very sophisticated bioinformatics analyses,” explains Domien Vanneste, first author of the study.
This study paves the way for future investigations that will evaluate the possibility of manipulating or controlling monocyte proliferation for therapeutic purposes, at the benefit of an enhanced health.
It may be better to let a mild fever run its course instead of automatically reaching for medication, new University of Alberta research suggests. Researchers found that, in fish models, untreated moderate fever helped them to quickly their infections, keep inflammation in check and repair damaged tissue. “We let nature do what nature does, and in this case it was very much a positive thing,” says ProfessorDaniel Barreda, immunologistand lead author on the study which is published in eLife.
Moderate fever is self-resolving, meaning that the body can both induce it and shut it down naturally without medication, Barreda explains. The health advantages of natural fever to humans still have to be confirmed through research, but the researchers say because the mechanisms driving and sustaining fever are shared among animals, it is reasonable to expect similar benefits are going to happen in humans.
That suggests the need to resist taking non-steroidal anti-inflammatory drugs at the first signs of a mild temperature, he says. “They take away the discomfort felt with fever, but you’re also likely giving away some of the benefits of this natural response.”
The study also sheds light on some benefits of moderate fever, which Barreda notes has been evolutionarily conserved across the animal kingdom for 550 million years. “Every animal examined has this biological response to infection.”
For the study, fish were given a bacterial infection and their behaviour was then tracked and evaluated using machine learning. Outward symptoms were similar to those seen in humans with fever, including immobility, fatigue and malaise. These were then matched to important immune mechanisms inside the animals.
The research showed that natural fever offers an integrative response that not only activates defences against infection, but also helps control it. The researchers found that fever helped to clear the fish of infection in about seven days – half the time it took for those animals not allowed to exert fever. Fever also helped to shut down inflammation and repair injured tissue.
“Our goal is to determine how to best take advantage of our medical advances while continuing to harness the benefits from natural mechanisms of immunity,” says Barreda.
While immunotherapy has been shown to greatly improve survival rates for certain types of cancer, in some cases, it can lead to a dangerous over-activation of the immune system. In a recent review published in Journal for ImmunoTherapy of Cancer, potential therapies have been identified, which might make it possible to continue with immunotherapy even when facing severe side effects.
The rare immunotherapy side effect of over-activation was only clinically recognised during regular clinical use rather than in clinical trials or animal experiments. To better understand this over-activation, Lisa Liu, Marco Gerling, and colleagues analysed data from all published international reports on this issue after cancer immunotherapy. Their findings indicate that potentially life-threatening inflammation may occur more frequently than previously thought, and might be treatable with existing drugs such as steroids or anti-inflammatory therapies commonly used for rheumatoid arthritis.
“It will be exciting to follow up on the main findings of our systematic review, says Marco Gerling at the Department of Biosciences and Nutrition, Karolinska Institutet and lead author.
“We believe that inhibition of a specific inflammatory molecule, interleukin-6, could allow patients to continue immunotherapy despite strong, systemic activation of the immune system”, he continues. “But we need more data to support the regular use of interleukin-6 inhibitors. We also want to thank Narcisa Hannerz and Sabine Gillsund from Karolinska University Library for their invaluable help with finding articles for this review.“
Shown here is a pseudo-colored scanning electron micrograph of an oral squamous cancer cell (white) being attacked by two cytotoxic T cells (red), part of a natural immune response. Photo by National Cancer Institute on Unsplash
When it comes to chronic infections and cancer, cytotoxic T cells play a central role in our defences. Research published in the journal Immunity has revealed that these cells can specialise into “sprinters” to fight a strong, short-term infection or into “marathon runners” for the long battle against chronic infections and cancer.
Professor Daniel Pinschewer at the Department of Biomedicine of the University of Basel led a study into understanding how cytotoxic T cells adapt to infection and cancer.
“These T cells can become specialised in two different ways: either as a kind of sprinter or as marathon runners,” explains Pinschewer. “However, the latter can also convert into sprinters at any time, in order to stamp out an infection.”
Chronic infections are a special case: the T cells are activated and a strong inflammatory response occurs at the same time. “This tends to ‘shock’ the T cells into developing into sprinters, which can only intervene effectively in the short term to remove infected cells,” says the virologist. “If all T cells behaved like that, our immune defences would break down pretty soon.”
Biological messenger counteracts the “shock”
The researchers examined how, in spite of this, the immune system is still able to provide enough T cells for the endurance race against chronic infections. According to their results, a biological messenger called interleukin-33 (IL-33) plays a key role. It allows the T cells to remain in their “marathon runner” state. “IL-33 takes away the shock of the inflammation, so to speak,” explains Dr Anna-Friederike Marx, lead author of the study.
In addition, the biological messenger causes the marathon T cells to proliferate, so that more endurance runners are available to combat the infection. “Thanks to IL-33, there are enough cytotoxic T cells around for the long haul that can still pull off a final sprint after their marathon,” says Marx.
The findings could help improve the treatment of chronic infections such as hepatitis C. It is conceivable that IL-33 could be administered to support an effective immune response. Thinking along the same lines, IL-33 could be one key to improving cancer immunotherapy, to enable T cells to wage an efficient and long-lasting offensive against tumour cells.
Scanning Electron Micrograph of Pseudomonas aeruginosa. Credit: CDC/Janice Carr
Pseudomonas aeruginosa bacteria are a common menace in hospital wards, causing life-threatening infections, and are often resistant to antibiotics. Researchers have discovered a mechanism that likely contributes to the severity of P. aeruginosa infections, which could also be a target for future treatments. The results were recently appeared in the journal EMBO Reports.
Many bacterial species use sugar-binding molecules called lectins to attach to and invade host cells. Lectins can also influence the immune response to bacterial infections. However, these functions have hardly been researched so far. A research consortium led by Prof Dr Winfried Römer at the University of Freiburg and Prof Dr Christopher G. Mueller at the CNRS/University of Strasbourg has investigated the effect of the lectin LecB from P. aeruginosa on the immune system. It found that isolated LecB can render immune cells ineffective: The cells are then no longer able to migrate through the body and trigger an immune response. The administration of a substance directed against LecB prevented this effect and led to the immune cells being able to move unhindered again.
LecB blockades immune cells
As soon as they perceive an infection, cells of the innate immune system migrate to a nearby lymph node, where they activate T and B cells, triggering a targeted immune response. LecB, according to the current study, prevents this migration. “We assume that LecB not only acts on the immune cells themselves in this process, but also has an unexpected effect on the cells lining the inside of the blood and lymph vessels,” Römer explains. “When LecB binds to these cells, it triggers extensive changes in them.” Indeed, the researchers observed that important structural molecules were relocated to the interior of the cells and degraded. At the same time, the cell skeleton became more rigid. “The cell layer thus becomes an impenetrable barrier for the immune cells,” Römer said.
An effective agent against LecB
Can this effect be prevented? To find out, the researchers tested a specific LecB inhibitor that resembles the sugar building blocks to which LecB otherwise binds. “The inhibitor prevented the changes in the cells, and T-cell activation was possible again,” Mueller said. The inhibitor was developed by Prof Dr Alexander Titz, who conducts research at the Helmholtz Institute for Pharmaceutical Research Saarland and Saarland University.
Further studies are needed to determine how clinically relevant the inhibition of the immune system by LecB is to the spread of P. aeruginosa infection and whether the LecB inhibitor has potential for therapeutic application. “The current results provide further evidence that lectins are a useful target for the development of new therapies, especially for antibiotic-resistant pathogens such as P. aeruginosa,” the authors conclude.
Fasting may be detrimental to fighting off infection, and could lead to an increased risk of heart disease, suggests a new study published in Immunity. The research in mouse models, shows that skipping meals triggers a response in the brain that negatively affects immune cells. The results could lead to a better understanding of how chronic fasting may affect the body long term.
“There is a growing awareness that fasting is healthy, and there is indeed abundant evidence for the benefits of fasting. Our study provides a word of caution as it suggests that there may also be a cost to fasting that carries a health risk,” says lead author Filip Swirski, PhD, Director of the Cardiovascular Research Institute at Icahn Mount Sinai. “This is a mechanistic study delving into some of the fundamental biology relevant to fasting. The study shows that there is a conversation between the nervous and immune systems.”
As part of a larger study on different fasting times affect the immune systems, researchers focused on the role of breakfast. They fed one group of mice breakfast right after waking up (breakfast is their largest meal of the day), and the other group had no breakfast. Researchers collected blood samples in both groups when mice woke up (baseline), then four hours later, and eight hours later.
Analysing the blood work, researchers saw a difference in the number of monocytes, which are white blood cells that are made in the bone marrow and travel through the body, where they play many critical roles, from fighting infections, to heart disease, to cancer.
At baseline, all mice had the same amount of monocytes. But after four hours, monocytes in mice from the fasting group were dramatically affected. Researchers found that 90% of these cells disappeared from the bloodstream, and the number further declined at eight hours. Meanwhile monocytes in the non-fasting group were unaffected.
In fasting mice, researchers discovered the monocytes travelled back to the bone marrow to hibernate. At the same time, production of new cells in the bone marrow diminished. The normally short-lived monocytes in the bone marrow survived longer as a consequence of staying in the bone marrow, and aged differently than the monocytes that stayed in the blood.
The researchers continued to fast mice for up to 24 hours, and then reintroduced food. The cells hiding in the bone marrow surged back into the bloodstream within a few hours, provoking heightened level of inflammation. Instead of protecting against infection, these altered monocytes were more inflammatory, making the body less resistant to fighting infection.
Researchers found that specific regions in the brain controlled the monocyte response during fasting. This study demonstrated that fasting elicits a stress response in the brain (feeling ‘hangry’) and this instantly triggers a large-scale migration of these white blood cells from the blood to the bone marrow, and then back to the bloodstream shortly after food is reintroduced.
Dr Swirski emphasised that while there is also evidence of the metabolic benefits of fasting, this new study is a useful advance in the full understanding of the body’s mechanisms.
“The study shows that, on the one hand, fasting reduces the number of circulating monocytes, which one might think is a good thing, as these cells are important components of inflammation. On the other hand, reintroduction of food creates a surge of monocytes flooding back to the blood, which can be problematic. Fasting, therefore regulates this pool in ways that are not always beneficial to the body’s capacity to respond to a challenge such as an infection,” explains Dr Swirski. “Because these cells are so important to other diseases like heart disease or cancer, understanding how their function is controlled is critical.”
Analysing an infant’s genome has allowed scientists to find a new way genetics influences the body’s antiviral response by studying a life-threatening disease caused by a common virus: herpes simplex virus 1 (HSV-1). The findings, published in Science Immunology, hold potential as a genetic marker doctors could use to gauge a child’s risk of herpes encephalitis, although such mutations are generally very rare in the population.
The researchers analysed genetic data from a patient with immunodeficiency and hospitalised at nine months old with herpes encephalitis, a rare but life-threatening brain inflammation after HSV-1 infection. They identified novel mutations in the gene GTF3A, and found that these mutations impair the innate immune response.
Many people are infected in childhood with the HSV-1 virus but the vast majority don’t suffer from encephalitis. The most common symptom of HSV-1 is oral cold sores, but many people show no signs at all. HSV-1 is more threatening to children and adults who are immunodeficient, whose immune system cannot control the virus well.
“Genetic and mechanistic analyses of uncommon viral diseases like herpes encephalitis are quite rare. In fact, the causes underlying severe herpes encephalitis are often unknown,” says Michaela Gack, PhD, FRIC’s scientific director. “This information provides us with invaluable insight into the fundamental molecular processes that govern our immune response and opens up opportunities for future research on severe disease outcomes.”
The Ghent research team led by Filomeen Haerynck, MD, PhD, reached out to Dr Gack’s team after finding the mutations in the gene. Dr Gack’s lab studies interactions between the human immune system and viruses on a molecular level.
The GTF3A mutations shape how cells respond to viral activity through the genetic makeup of a protein called TFIIIA. TFIIIA plays a role in helping a human enzyme produce certain types of RNA that can determine specific functions inside cells. Some RNAs can elicit an anti-herpes viral immune response.
Dr Gack’s team tested cells that have the mutations, and found that because of defects in certain immunostimulatory RNAs, the cells were more susceptible to HSV-1 infection and lost the ability to control the HSV-1 virus.
The affected gene is part of the body’s defence system that produces interferons to combat viruses. Interferons are crucial to the human immune response and for suppressing virus infection and spread.
This new genetic pathway could be helpful in understanding the immune response to other viruses, like Epstein-Barr virus, a common virus linked to mononucleosis and associated with certain types of cancer and multiple sclerosis.
“Understanding the molecular processes underlying antiviral responses is key to treating or possibly preventing severe viral infections that change patients’ and families’ lives,” Dr Gack said. “Our findings on critical immune defence proteins may translate into new therapies in the future.”
The immune systems of preterm babies are especially weak, making them more vulnerable to infection. A new study published in JCI Insight suggests that this vulnerability instead stems from an immune signalling pathway being suppressed, perhaps due to a requirement for it for successful foetal development in utero.
The earlier babies are born, the higher the risk of life-threatening complications. Infections can lead to sepsis and are among the most frequent causes of death.
“In the case of very prematurely born infants, a bacterial infection can lead to death within hours,” says LMU physician Prof Markus Sperandio. The physiologist and former paediatrician and neonatologist researches the causes of this high susceptibility to infection together with his team at LMU’s Biomedical Center Munich. Now the researchers have demonstrated that an immunostimulatory signalling pathway is suppressed in the developing immune system.
In preterm infants, neutrophils ‘turned off‘
Sperandio had already shown in earlier studies that, in the foetus and in newborns, neutrophils do not work as in adults. Unlike in adults, foetal and neonatal neutrophils do not manage to sufficiently attach to the walls of blood vessels and extravasate into inflamed tissue. This is necessary, however, to trigger an inflammatory response and thus initiate immune defence.
Now the LMU researchers, working in collaboration with the Children and Women’s Clinic at University of Munich Hospital, have investigated which mechanisms are behind this immaturity. By means of a so-called transcriptomic analysis, they compared the gene activity of neutrophils in umbilical cord blood of premature and full-term babies with adult neutrophils. Compared to adults, there is a lot of gene activity in premature and full-term infants that counteracts immune defence. “In this case, these neutrophils act as if they were switched off,” says Sperandio.
Balance shift of immunoregulatory signalling pathways
This particularly affects signals transmitted via the NF-κB signalling pathway, which plays a decisive role in immune and inflammatory responses. It consists of two possible pathways for signals: one that promotes inflammation and one that can suppress it. Therefore, the activity of these two pathways must be finely balanced for proper regulation of the immune response.
“Our experiments have shown that this balance is shifted towards the anti-inflammatory pathway in foetal and neonatal neutrophils,” says Sperandio. “Whereas this regulation of neutrophil function is clearly a requirement for normal foetal growth in utero, it leads to immune defence problems in prematurely born infants who have to adapt ‘too soon’ to the world outside the uterus.” To what extent these findings will be a springboard for new therapeutic approaches in the future remains to be seen. “Due to the complex processes in the growing foetal and neonatal organism, maturation-adapted therapies are conceivable but remain a long way off at this stage,” says Sperandio.
A new approach for treating systemic lupus erythematosus (SLE) could lie in targeting iron metabolism in immune system cells. Researchers found that blocking an iron uptake receptor reduces disease pathology and promotes the activity of anti-inflammatory regulatory T cells in a mouse model of SLE. The findings were published in the journal Science Immunology.
Treatments for lupus aim to control symptoms, reduce immune system attack of tissues, and protect organs from damage. Only one targeted biologic agent has been approved for treating SLE, belimumab in 2011.
“It has been a real challenge to come up with new therapies for lupus,” said Jeffrey Rathmell, PhD, Vanderbilt University professor. “The patient population and the disease are heterogeneous, which makes it difficult to design and conduct clinical trials.”
Rathmell’s group has had a long-standing interest in lupus as part of a broader effort to understand mechanisms of autoimmunity.
When postdoctoral fellow Kelsey Voss, PhD, began studying T cell metabolism in lupus, she noticed that iron appeared to be a “common denominator in many of the problems in T cells,” she said. She was also intrigued by the finding that T cells from patients with lupus have high iron levels, even though patients are often anaemic.
“It was not clear why the T cells were high in iron, or what that meant,” said Voss.
To explore T cell iron metabolism in lupus, Voss and Rathmell drew on the expertise of other investigators at VUMC.
First, Voss used a CRISPR genome editing screen to evaluate iron-handling genes in T cells. She identified the transferrin receptor, which imports iron into cells, as critical for inflammatory T cells and inhibitory for anti-inflammatory regulatory T cells.
The researchers found that the transferrin receptor was more highly expressed on T cells from SLE-prone mice and T cells from patients with SLE, which caused the cells to accumulate too much iron.
“We see a lot of complications coming from that – the mitochondria don’t function properly, and other signalling pathways are altered,” Voss said.
An antibody that blocks the transferrin receptor reduced intracellular iron levels, inhibited inflammatory T cell activity, and enhanced regulatory T cell activity. Treatment of SLE-prone mice with the antibody reduced kidney and liver pathology and increased production of the anti-inflammatory factor, IL-10.
“It was really surprising and exciting to find different effects of the transferrin receptor in different types of T cells,” Voss said. “If you’re trying to target an autoimmune disease by affecting T cell function, you want to inhibit inflammatory T cells but not harm regulatory T cells. That’s exactly what targeting the transferrin receptor did.”
In T cells from patients with lupus, expression of the transferrin receptor correlated with disease severity, and blocking the receptor in vitro enhanced production of IL-10.
Since the transferrin receptor mediates iron uptake in many cell types, the researchers want to develop transferrin receptor antibodies that bind specifically to T cells, to minimise off-target effects. They are also interested in studying the details of their unexpected discovery that blocking the transferrin receptor enhances regulatory T cell activity.
