Could umbilical cord cells offer a new treatment?

Could umbilical cord cells offer a new treatment?

  • June 14, 2021

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New research points to umbilical cord cells as a potential treatment avenue for COVID-19. Photo editing by Stephen Kelly; luismmolina/Getty Images
  • A small clinical trial suggests stem cells from umbilical cords can reduce the mortality rate of COVID-19 patients on ventilators.
  • The cells may help calm the cytokine storm implicated in acute respiratory distress syndrome.
  • The treatment appears particularly effective among patients with underlying health conditions such as obesity, kidney disease, and diabetes.

In the early months of the pandemic in 2020, the mortality rate of patients with pneumonia due to COVID-19 in the intensive care unit (ICU) of Persahabatan Central Hospital in Jakarta, Indonesia, reached 87%.

“[T]his situation necessitated that clinicians fashion a breakthrough therapy to increase the survival of patients in the ICU,” write Professor Ismail Hadisoebroto Dilogo, M.D., Ph.D., and his colleagues in the journal Stem Cells Translational Medicine.

In their paper, Prof. Dilogo and his team, specialists in stem cell therapy at Cipto Mangunkusumo Central Hospital in Jakarta, describe a clinical trial of the treatment they devised.

Between May 1 and October 10, 2020, the trial randomly assigned 40 patients with COVID-19 to receive either injections of umbilical cord stem cells in saline solution or injections of saline alone.

All the patients had severe pneumonia and were on ventilators in the ICU at four hospitals in Jakarta.

Out of the 20 patients who received injections of stem cells, 10 survived, while only 4 out of 20 patients survived in the control group.

The researchers report that among patients with underlying health conditions, those who received the treatment were 4.5 times as likely to survive compared with controls.

There were no adverse events that the scientists could attribute to the treatment.

The leading cause of death in COVID-19 is acute respiratory distress syndrome, which may be due to an overreaction of the immune system or “cytokine storm” — although this remains controversial.

The type of stem cell that researchers used in the new trial, called a mesenchymal stromal cell or MSC, has shown promise for treating lung diseases such as asthma and chronic obstructive pulmonary disease.

MSCs appear to improve these conditions by toning down the immune system’s inflammatory responses.

The cells are found in several tissues in the body, including bone marrow and adipose tissue, but also the umbilical cord.

The latter is a more freely available, readily accessible source. In addition, the recipient’s immune system is less likely to reject the umbilical cord cells.

In their paper, Prof. Dilogo and his co-authors conclude that MSCs may increase survival rates among critically ill patients by switching their immune systems to an anti-inflammatory mode.

They report that circulating levels of a pro-inflammatory cytokine called interleukin 6 were significantly reduced in patients who received infusions of MSCs compared with control patients.

Interestingly, the antibody-drug tocilizumab — which blocks IL-6 receptors — is one of the few treatments found to improve survival in severe COVID-19.

In contrast to the few other studies of MSCs in COVID-19, published in April 2020 and August 2020, the current trial uses unaltered or “naive” cells.

The earlier studies from China, which were on a smaller scale, used cells that had undergone a complex procedure to strip them of ACE-2 receptors.

These are the receptors that SARS-CoV-2, the virus that causes COVID-19, uses to break into its host cells in the human body.

However, the new trial suggests that this precaution is unnecessary to reap the potential benefits of the treatment, which greatly simplifies the procedure.

The researchers believe their approach could lead to an effective therapy for COVID-19 patients in intensive care who do not respond to conventional treatment.

“Reflecting on our study result, we will continue to explore the usage of MSC in COVID-19 cases,” said Bernadus Riyan, M.D., Prof. Dilogo’s assistant.

He told Medical News Today that Prof. Dilogo and his team hope to make MSCs from umbilical cords more widely available to save the lives of more critically ill patients in Indonesia.

The authors acknowledge their study had several limitations.

For example, researchers need to conduct more clinical trials involving larger numbers of patients to confirm the results.

In addition, the authors report that they did not apply strict criteria to determine how long patients in each experimental group received treatment in the ICU. This hidden variable may have biased the results.

For live updates on the latest developments regarding the novel coronavirus and COVID-19, click here.

Freiburg researchers receive ERC funding to develop and test immunostimulatory drug candidates

Macrophages can aid tumor growth by distracting cancer-killing CD8+ T cells

  • June 11, 2021

A Ludwig Cancer Research study adds to growing evidence that immune cells known as macrophages inhabiting the body cavities that house our vital organs can aid tumor growth by distracting the immune system’s cancer-killing CD8+ T cells.

Reported in the current issue of Cancer Cell and led by Ludwig investigators Taha Merghoub and Jedd Wolchok at Memorial Sloan Kettering (MSK) and Charles Rudin of MSK, the study shows that cavity-resident macrophages express high levels of Tim-4, a receptor for phosphatidylserine (PS), a molecule that they surprisingly found on the surface of highly activated, cytotoxic and proliferative CD8+ T-cells.

“We believe T-cells that infiltrate the peritoneal cavity can be distracted by the interaction with Tim-4-expressing macrophages,” explained study first author Andrew Chow, an assistant attending physician at the Ludwig Collaborative Laboratory at MSK.

The researchers also show that blocking Tim-4 in mouse models of cancer can prevent this distractive interaction and enhance the effectiveness of immunotherapies.

“I think in patients who have these serous cavity macrophages expressing high levels of Tim-4, blocking Tim-4 will make immune based therapies more effective,” Merghoub, co-director of the Ludwig Collaborative Laboratory at MSK, said.

Just as people living in different cities might have distinct customs or accents, the macrophages in our bodies can adopt specialized functions and respond to disease differently depending on which tissue they inhabit. Scientists are increasingly interested in such localized responses because macrophage activities can influence recovery from illness or injury and responses to therapy.

Merghoub, Wolchok, Rudin, Chow and colleagues began exploring the role of macrophages in tumor immunosuppression after noticing that cancer patients with lesions in their pleural and peritoneal cavities-;which house the lungs and organs of the gastrointestinal tract, respectively-;were substantially less responsive to immune checkpoint blockade therapy, which stimulates a CD8+ T cell attack on tumors.

“That told us there was something immunosuppressive in these cavities, so we went hunting for what that could be,” Chow said.

Previous studies have shown that other immunosuppressed sites in the body, such as the liver and bone, harbor macrophages expressing high levels of Tim-4. Others have shown that macrophages living in the pleural and peritoneal cavities of mice also exhibit a strong Tim-4 signal.

The researchers therefore suspected that cavity-resident macrophages might impair the anti-tumor activity of CD8+ T cells through the actions of Tim-4.

These suspicions were partly vindicated when the researchers analyzed the cavity macrophages of human lung cancer patients and found that while Tim-4 levels varied between individuals, those with higher levels of the receptor tended to have a reduced presence of CD8+ T cells that had features of responding to the tumor.

Based on these observations, the researchers explored whether blocking Tim-4 would enhance the efficacy of PD-1 blockade therapies in a pre-clinical mouse model of colon and lung cancer in the peritoneal cavity.

“We showed that you get the best tumor protection when you block both molecules,” Chow said.

While blocking Tim-4 alone didn’t reduce the number of tumors or improve survival in the mice, it did enhance the tumor protection afforded by PD-1 blockade and boost the numbers of CD8+ T cells in the peritoneal cavity. The researchers also showed that Tim-4 blockade reduces immunosuppression in adoptive T-cell therapy, in which tumor-targeting T-cells are isolated and selectively grown in a lab before they’re reinfused into the patient.

“Together, these results suggest that Tim-4 blockade is a strategy to improve immunotherapy, regardless of whether you’re trying to boost your immune response through immune checkpoint blockade therapy or via adoptive T-cell therapy,” said Chow.

For Merghoub, the new findings demonstrate the need to better understand the diversity of immune landscapes in and around tumors. “In the same way we profile tumor genomes to guide the use of small molecule inhibitors for targeted therapies, we need to profile the immune landscapes of tumors and personalize immune-based therapies on the basis of such studies,” he said.

UCLA: Antidepressant Drug May Help Fight Cancer

UCLA: Antidepressant Drug May Help Fight Cancer

  • June 11, 2021

LOS ANGELES (CNS) – Results of a new study released today by UCLA suggests that a class of drug commonly prescribed to treat depression might have another health benefit by helping the immune system attack cancer.

The class of drug called monoamine oxidase inhibitors work by boosting levels of serotonin, the brain’s “happiness hormone,” according to researchers.

“MAOIs had not been linked to the immune system’s response to cancer before,” said Lili Yang, senior author of the study and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

“What’s especially exciting is that this is a very well-studied and safe class of drug, so repurposing it for cancer isn’t as challenging as developing a completely new drug would be.”

The findings are reported in two papers, which are published in the journals Science Immunology and Nature Communications.

Recent advances in understanding how the human immune system naturally seeks out and destroys cancer cells, as well as how tumors try to evade that response, has led to new cancer immunotherapies — drugs that boost the immune system’s activity to try to fight cancer.

In an effort to develop new cancer immunotherapies, Yang and her colleagues compared immune cells from melanoma tumors in mice to immune cells from cancer-free animals. Immune cells that had infiltrated tumors had much higher activity of a gene called monoamine oxidase A, or MAOA. MAOA’s corresponding protein, called MAO-A, controls levels of serotonin and is targeted by MAOI drugs.

“For a long time, people have theorized about the cross-talk between the nervous system and the immune system and the similarities between the two,” said Yang, who is also a UCLA associate professor of microbiology, immunology and molecular genetics and a member of the UCLA Jonsson Comprehensive Cancer Center.

“So it was exciting to find that MAOA was so active in these tumor-infiltrating immune cells.”

Copyright 2021, City News Service, Inc.

Non-altered birth cord cells boost survival of critically ill COVID-19 patients

Non-altered birth cord cells boost survival of critically ill COVID-19 patients

  • June 8, 2021

IMAGE

IMAGE: Ismail Hadisoebroto Dilogo, professor of medicine at Cipto Mangunkusumo Central Hospital-Universitas Indonesia, corresponding author of the study.
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Credit: AlphaMed Press

Durham, NC – Critically ill COVID-19 patients treated with non-altered stem cells from umbilical cord connective tissue were more than twice as likely to survive as those who did not have the treatment, according to a study published today in STEM CELLS Translational Medicine.

The clinical trial, carried out at four hospitals in Jakarta, Indonesia, also showed that administering the treatment to COVID-19 patients with an added chronic health condition such as diabetes, hypertension or kidney disease increased their survival more than fourfold.

All 40 patients who took part in the double-blind, controlled, randomized study were adults in intensive care who had been intubated due to COVID-19-induced pneumonia. Half were given intravenous infusions containing umbilical mesenchymal stromal cells, or stem cells derived from the connective tissue of a human birth cord, and half were given infusions without them.

The survival rate of those receiving the stem cells was 2.5 times higher and climbed even more – 4.5 times – in the COVID-19 patients who had other chronic health conditions, said Ismail Hadisoebroto Dilogo, professor of medicine at Cipto Mangunkusumo Central Hospital-Universitas Indonesia and research team member.

The stem cell infusion also was found to be safe and well-tolerated with no life-threatening complications or acute allergic reactions in seven days of post-infusion monitoring, he said.

Previous clinical trials have shown that treating COVID-19 pneumonia patients with stem cells from umbilical cord connective tissue may help them survive and recover more quickly, but the Indonesian study is the first to treat intubated, critically ill COVID-19 pneumonia patients with a naive, or non-genetically manipulated, form of the stem cells.

“Unlike other studies, our trial used stem cells obtained through explants from actual umbilical cord tissue and we did not manipulate them to exclude ACE2, a cellular protein thought to be an entry point for COVID-19,” Dilogo said.

Some research suggests that one of the main causes of acute respiratory distress in COVID-19 patients is “cytokine storm,” a condition in which infection prompts the body’s immune system to flood the bloodstream with inflammatory proteins.

“The exact cause of cytokine storm is still unknown, but our study indicates that the presence of non-manipulated umbilical cord stromal stem cells improves patient survival by modulating the immune system toward an anti-inflammatory immune state,” Dilogo said.

Since there is no cure for COVID-19, supportive care has been the only help available for patients who are critically ill with the virus.

“Although our study focused on a small number of patients, we think this experimental treatment could potentially lead to an effective adjuvant therapy for COVID-19 patients in intensive care who do not respond to conventional supportive treatment,” he said.

Dilogo’s research team launched the clinical trial last year after the COVID-19 occupancy rate in Jakarta’s intensive care units climbed to 80 percent and the mortality rate of critically ill COVID-19 pneumonia patients in the ICUs reached 87 percent.

“This study, which assessed the potential therapeutic effect of human umbilical-cord mesenchymal stem cells on critically-ill COVID-19 patients, provides promising results that could inform a potential treatment to increase survival rates,” said Anthony Atala, M.D., Editor-in-Chief of STEM CELLS Translational Medicine and Director of the Wake Forest Institute for Regenerative Medicine. “Having additional potential therapies, such as MSCs, could be highly beneficial for these patients.”

###

The full article, “Umbilical Cord Mesenchymal Stromal Cells as Critical COVID-19 Adjuvant Therapy: A Randomized Controlled Trial” can be accessed at https://stemcellsjournals.onlinelibrary.wiley.com/doi/abs/10.1002/sctm.21-0046.

About STEM CELLS Translational Medicine: STEM CELLS Translational Medicine (SCTM), co-published by AlphaMed Press and Wiley, is a monthly peer-reviewed publication dedicated to significantly advancing the clinical utilization of stem cell molecular and cellular biology. By bridging stem cell research and clinical trials, SCTM will help move applications of these critical investigations closer to accepted best practices. SCTM is the official journal partner of Regenerative Medicine Foundation.

About AlphaMed Press: Established in 1983, AlphaMed Press with offices in Durham, NC, San Francisco, CA, and Belfast, Northern Ireland, publishes two other internationally renowned peer-reviewed journals: STEM CELLS® (http://www.StemCells.com), celebrating its 39th year, is the world’s first journal devoted to this fast paced field of research. The Oncologist® (http://www.TheOncologist.com), also a monthly peer-reviewed publication, entering its 26th year, is devoted to community and hospital-based oncologists and physicians entrusted with cancer patient care. All three journals are premier periodicals with globally recognized editorial boards dedicated to advancing knowledge and education in their focused disciplines.

About Wiley: Wiley, a global company, helps people and organizations develop the skills and knowledge they need to succeed. Our online scientific, technical, medical and scholarly journals, combined with our digital learning, assessment and certification solutions, help universities, learned societies, businesses, governments and individuals increase the academic and professional impact of their work. For more than 200 years, we have delivered consistent performance to our stakeholders. The company’s website can be accessed at http://www.wiley.com.

About Regenerative Medicine Foundation (RMF): The non-profit Regenerative Medicine Foundation fosters strategic collaborations to accelerate the development of regenerative medicine to improve health and deliver cures. RMF pursues its mission by producing its flagship World Stem Cell Summit, honouring leaders through the Stem Cell and Regenerative Medicine Action Awards, and promoting educational initiatives.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

How new insights into skull-based immune cells could inspire treatments for brain disease

How new insights into skull-based immune cells could inspire treatments for brain disease

  • June 4, 2021

Some immune cells in the brain protect against disease, while others cause inflammation and other problems that can actually lead to disease. Researchers at Washington University School of Medicine in St. Louis are shedding light on the differences between these immune cell populations in two new studies.

The researchers discovered that some immune cells originate in the skull and migrate to the meninges—the tissues that line the brain and spinal cord—without passing through the bloodstream. The sole job of those skull-based immune cells is to shield the brain from disease, they explained in the journal Science.

The discovery could boost drug development for a wide range of brain diseases, the researchers believe.

“There has been this gap in our knowledge that applies to almost every neurological disease: neuro-COVID, Alzheimer’s disease, multiple sclerosis, brain injury, you name it,” said senior author Jonathan Kipnis, Ph.D., professor of pathology and immunology at Washington University, in a statement. “We knew immune cells were involved in neurological conditions, but where were they coming from? What we’ve found is that there’s a new source that hasn’t been described before for these cells.”

Kipnis and his team had previously demonstrated that immune cells in the meninges shield the brain from harmful invaders. For one of the two new studies, he and his colleagues focused on “innate” immune cells, which cause inflammation that can heal injuries and defend against disease. But these cells can also cause damage and contribute to diseases like Alzheimer’s.

RELATED: How the brain’s immune cells could guide treatment of neurodegenerative diseases

A second Washington University team zeroed in on “adaptive” immune cells, which can destroy viruses and cancer but sometimes mistakenly attack healthy tissues, causing diseases like multiple sclerosis. The researchers discovered that B cells in the adaptive immune system originate and mature in the skull’s bone marrow.

Those B cells learn how to tell the difference between normal proteins and those that indicate the presence of disease. Because they migrate from the skull to the brain via channels other than blood, they maintain that ability to patrol the central nervous system without attacking normal proteins, the researchers explained.

A separate set of B cells does travel into the meninges from the blood—and these cells are not as good at distinguishing normal from abnormal proteins, according to that team. Meanwhile, Kipnis and his colleagues discovered that innate meningeal myeloid cells, which flood injured brain tissues, are inflammatory when they travel from the blood.

The influence of immune cells in the brain on neurological diseases is an area of intense research, much of which has been focused on microglia, a subset of myeloid cells that remove debris. Last year, for example, researchers at Stanford University spun off a startup, Tranquis Therapeutics, to target dysfunctional microglia in neurologic disorders. Its lead asset is a drug that restores a downregulated metabolic pathway in myeloid cells.

The Washington University researchers believe their discoveries about the origins of immune cells in the brain could be used to design new therapies for inflammatory brain disorders. “The location of these cells in the skull makes them relatively accessible, and opens up the possibility of designing therapies to alter the behavior of these cells and treat neuro-immune conditions,” Kipnis said.

Natural killer cells lull tumours into dormancy

Natural killer cells lull tumours into dormancy

  • June 2, 2021

Efforts to treat tumours that have spread from their initial site in the body to grow elsewhere are often unsuccessful. Such tumours, called metastases, are the main cause of cancer-related deaths, so finding a way to control them is crucial to meeting this medical need. Before metastases begin to grow, cancer cells might have already migrated from the primary tumour to seed various other sites (a process called metastasis), where they can remain dormant for long periods of time. Surveillance by immune cells is known to help to maintain this dormancy1, but the mechanisms involved in the switch from dormancy to the growth of metastases have been unclear — until now. Writing in Nature, Correia et al.2 report the pivotal role of natural killer (NK) cells in controlling the development of liver metastases arising from breast cancer.

NK cells are part of the innate branch of the immune system. They can kill other cells and produce soluble messenger molecules, called cytokines and chemokines, that regulate immune responses3. The ability of NK cells to detect and eliminate a wide array of tumour cells directly, and their capacity to shape antitumour immune responses by making cytokines or chemokines, have led to the development of clinical strategies that harness their anticancer functions35.

Several studies have suggested that NK cells specialize in eliminating metastases rather than targeting tumour cells at their primary site of growth6. For some cancers, people who have more tumour-infiltrating NK cells seem to have fewer metastases, as seen in those with cancers such as gastrointestinal sarcoma, and gastric, colorectal, renal or prostate carcinoma3,6. The depletion or dysfunction of NK cells in mice also results in an increase in metastases3. By contrast, when their normal regulation is removed, NK cells protect against the spread of tumours to the liver and lungs7. Tumour cells entering dormancy downregulate their expression of ligand molecules that can activate NK cell receptors, and become resistant to killing mediated by NK cells8.

Correia and colleagues decided to further investigate the composition and dynamics of tumour cells in dormancy. One approach they took was to study the gene-expression profile of human and mouse breast cancer cells transplanted into mice. These cells underwent metastasis to reach sites such as the liver, where they became dormant tumour cells. The authors assessed genes expressed by cells in the vicinity of the dormant tumour cells in the surrounding stromal tissue. These data revealed a gene signature associated with responses mediated by NK cells. Furthermore, Correia et al. compared the areas around dormant tumour cells with those in tumour-free livers, and found that NK cells were the only type of immune cell to increase in number during dormancy. This suggests that NK cells have a crucial role in events that block the reawakening of dormant tumour cells (Fig. 1).

Figure 1

Figure 1 | Interactions that affect the dormancy of tumour cells. Correia et al.2 report mouse and human evidence indicating that a type of immune cell called a natural killer (NK) cell has a key role in preventing the growth of spreading tumour cells, called metastases. a, The molecule IL-15 drives NK cells to proliferate, and these cells secrete the protein IFN- γ, which keeps breast cancer cells that have migrated to the liver in a dormant state. b, Exit from this state of dormancy is associated with activated hepatic stellate cells, which secrete the molecule CXCL12. CXCL12 binds to the CXCR4 receptor on NK cells. This results in NK cells ceasing to divide and stops them from promoting tumour dormancy. The tumour cells proliferate as a consequence.

Consistent with this hypothesis, the authors report that depleting NK cells in a mouse tumour model then led to higher levels of metastases in the liver. However, if NK cells were boosted using the cytokine IL-15, this prevented the formation of liver metastases and tumour cells remained dormant. The authors’ results demonstrate that the size of the pool of NK cells in the liver environment determines whether dormancy occurs or metastases form.

The liver environment associated with dormant tumour cells contained NK cells producing the cytokine interferon-γ (IFN-γ). Correia and colleagues report that, in vitro, adding IFN-γ can nudge cancer cells into dormancy — consistent with the idea that IFN-γ has a key role in controlling the cancer dormancy mediated by NK cells.

Might other factors disrupt NK cells and thereby promote the formation of metastases? A clue to this came from the authors’ discovery that a pool of activated hepatic stellate cells found in the mouse liver increased when tumours switched from dormancy to forming metastases. Hepatic stellate cells have been identified as the main disease-driving population of cells for a condition called hepatic fibrosis9, in which the liver becomes damaged and scarred. These changes often precede tumour formation. The accumulation of activated hepatic stellate cells occurs at the same time as a decline in NK cells, owing to a decrease in NK-cell proliferation. The authors’ results suggest that activated hepatic stellate cells promote metastases in the liver by inhibiting NK cells, thereby disrupting cancer dormancy.

Correia et al. found that hepatic stellate cells secrete the chemokine CXCL12, which has been implicated in aiding the directional migration of breast cancer cells10. Organs that express the highest levels of CXCL12 are the most common sites of metastasis in human breast cancer10. Human NK cells in the liver have a receptor, called CXCR4, that recognizes CXCL12. Correia and colleagues report that activated hepatic stellate cells hamper the function of NK cells in the liver through CXCL12–CXCR4 interactions that halt the proliferation of NK cells, thereby tipping the scales from tumour dormancy to the promotion of metastasis. This study thus reveals a previously unknown function of CXCL12 in altering NK-cell-mediated immunity, in addition to its known effects on tumour cells10.

The authors next examined pairs of human biopsy specimens from metastases and healthy adjacent liver tissue, taken from people with breast cancer. Consistent with the data from mice, the analysis showed that activated hepatic stellate cells accumulated in metastases, and that their abundance was inversely correlated with that of NK cells. The authors’ analysis of published gene-expression data for colorectal cancer that has metastasized to the liver revealed the same association, suggesting that this cellular crosstalk might be relevant for the growth of other types of spreading cancer.

Several questions remain to be answered. For example, the mechanisms underlying the accumulation of NK cells associated with dormant tumour cells and the triggering of IFN-γ production in these circumstances remain to be fully determined. It is not completely clear how CXCL12 that is secreted by activated hepatic stellate cells hinders the function of NK cells. Furthermore, determining whether the CXCL12–CXRC4 axis awakens dormant tumour cells in humans is of utmost importance, and, if so, in which types of cancer.

Finally, the similarities between NK cells and another sort of immune cell called type 1 innate lymphoid cells (ILC1) should prompt further investigation of the role of ILC1 in controlling metastasis3. Indeed, these cells have a complex role in tumour responses11,12. Correia et al. excluded ILC1 as having a role in controlling metastases, because they observed no notable changes in the level of these cells when comparing tumour dormancy and metastases in the liver. However, the lack of a specific ILC1-deficient mouse model means that it is not possible to precisely dissect the respective roles of NK cells and ILC1 in the control of metastasis, leaving a key question unresolved.

By showing that the IFN-γ-driven effects of NK cells maintain breast cancer cells in a dormant state, Correia and colleagues have revealed that NK cells have other and previously unsuspected anticancer capacities. This finding paves the way for the development of cancer treatment strategies that prevent dormant reservoirs of tumour cells from awakening. For instance, molecules that strongly stimulate the IL-15 pathway in NK cells are already available. These IL-15 superagonists, such as ALT-803 or NKTR-255, are being tested in clinical trials3,5, and the rationale for their use should now also take into account the role of NK cells in controlling dormant tumour cells.

Furthermore, drugs that inhibit CXCR4 are being developed. It would be interesting to determine whether these inhibitors could help to sustain the activity of NK cells in maintaining tumour dormancy. In addition, engineered antibodies called NK cell engagers, which can stimulate NK cells and form a bridge that connects them to tumour cells, offers another way to promote the function of NK cells13. Current clinical trials are also testing various approaches to manipulate NK cells for therapeutic benefit35. Besides the well-characterized effects of NK cells in tumour immunity, Correia and colleagues’ work further highlights the possible advantages of harnessing NK cells to target cancers.

Competing Interests

E.V. is a shareholder and employee of Innate Pharma.

Why bone marrow cells may mean coronavirus antibodies ‘last years’

Why bone marrow cells may mean coronavirus antibodies ‘last years’

  • May 28, 2021

Immunity against Covid-19 may last for years in people who have recovered from the virus or received a vaccine, two new studies suggest.

Cells found in bone marrow that are generated during an immune response “may retain a memory of the virus”, The Times reports, meaning they “can produce long-lasting antibodies as a defence against future infections”.

Research published this week in Nature and on BioRxiv, a pre-print online research site, both suggest “these cells strengthen over a period of at least a year”, suggesting people “may not need booster shots… for a considerable period of time”, the paper adds.

The studies “looked at people who had been exposed to the coronavirus about a year earlier” and found “cells that retain a memory of the virus persist in the bone marrow and may churn out antibodies whenever needed”, The New York Times (NYT) says.

“These so-called memory B cells continue to mature and strengthen for at least 12 months” after infection or vaccination, the paper adds.

“It’s normal for antibody levels to go down after acute infection, but they don’t go down to zero; they plateau,” Ali Ellebedy, an assistant professor at Washington University in St Louis who led the Nature study, told The Times.

“These cells have been generated as part of the immune response and they live at this stage for a very long period and continue to secrete antibodies.

“These cells are not dividing. They are quiescent, just sitting in the bone marrow and secreting antibodies. They have been doing that ever since the infection resolved, and they will continue doing that indefinitely.”

Ellebedy’s study monitored antibody levels in 77 patients who tested positive for Covid-19, finding that antibody levels in their bone marrow fell after four months but were still present after 11 months.

The findings will serve to “soothe fears that immunity to the virus is transient”, the NYT says, “as is the case with coronaviruses that cause common colds”. However, the results “may not apply to protection derived from vaccines alone” as “immune memory is likely to be organised differently after immunisation” when compared with natural infection.

Nonetheless, the studies will “give cheer to those concerned that antibodies produced after infection are short lived”, The Times adds, with Ellebedy suggesting that people who recover from the virus and are vaccinated may be “super protected”.

The two studies come after a separate study that found “the Oxford/AstraZeneca Covid-19 vaccine works well as a third booster shot”, the Financial Times reports, strengthening suggestions that the cheap, easily transportable jab could be used to provide an immunity boost.

A third jab was found “to boost participants’ antibodies to the coronavirus’s spike protein in an upcoming study by Oxford university”, the paper adds, despite concerns that “repeated use of the adenovirus vector – an inactivated cold virus – could stop the immune system recognising the virus’s spike protein”.

The study “kills all these arguments that you can’t use adenoviruses more than once”, a person familiar with the findings told the FT, adding that the immune response to a third shot was “unbelievable” and strong enough to “blow through almost any variant”.

153 years after discovery of the immune system's dendritic cells, scientists uncover a new subset

153 years after discovery of the immune system’s dendritic cells, scientists uncover a new subset

  • May 27, 2021
dendritic cell
Artistic rendering of the surface of a human dendritic cell illustrating sheet-like processes that fold back onto the membrane surface. Credit: National Institutes of Health (NIH)

When pathogens invade or tumor cells emerge, the immune system is alerted by danger signals that summon a key battalion of first responders, the unsung heroes of the immune system—a population of starfish-shaped sentinels called dendritic cells.

Without them, coordination of the immune response would be slower and less-well organized. Yet even in the face of such an indispensable role, it has taken until now to discover how a sub-population of these doesn’t perish after completing their primary job in the immune system.

Dendritic cells were discovered in 1868, and at that time were misunderstood and wrongly categorized as members of the nervous system. But immunologists now know there are different types of these cells, even though they all look alike and have roughly the same job as sentinels in the immune system –on patrol 24/7, hunting down infiltrating causes of infection and disease. What separates one group from another, scientists in Germany have just found, is their response to certain signaling molecules and how long they survive in tissues and the blood.

First off, the shape is no accident of nature. It allows these cells to perform their primary role, which involves obtaining microscopic samples—antigens—from an infiltrator slated for destruction. Dendritic cells engulf snippets of the invader and literally present those antigens to key warriors of the immune system.

These highly mobile cells travel to sites where disease-killing reside to present their samples, introducing T cells, for example, to the enemy that awaits. Formally, the activity of presenting the sample to T cells is called antigen presentation. For all the work involved with alerting the body to danger, a major group of dendritic cells is programmed to die after a job well done.

Now, in a groundbreaking series of studies, a large team of researchers from throughout Germany has discovered why a unique population of dendritic cells doesn’t die after antigen presentation. The sub-population continues to stimulate parts of the immune system to aid the fight against invasive viruses, bacteria or potentially deadly .

The finding is likely to be viewed as welcome news in a world beset by a pandemic virus and a slew of worrisome variants. All have stoked concerns about the longevity of immunity triggered by COVID-19 vaccines. Another major role of dendritic cells, as it turns out, is marshaling immune forces in response to vaccination.

To understand the importance of the new research, it’s first necessary to detour away from the new finding to delve instead into a primer on the two divisions of the human immune system: the innate and the adaptive.

Also, to fully grasp the research, it’s important for another quick lesson: Dendritic cells 101. The new finding, scientists say, promises to change how the cells are defined going forward.

The innate immune system is composed of the big eaters, the so-called professional phagocytes that devour as much of an invading enemy as possible, chewing them into harmless trash. This part of the immune system also releases a tsunami of cytokines and other inflammatory molecules. Adaptive immunity is anchored by the big daddies of the immune response, mainly the various populations of B and T cells.

Dendritic cells, or DCs as they’re also known, are the antigen-presenting population, which simply means they engulf a sample of an invader and race to present it to disease-fighting warriors of the adaptive immune system. But dendritic cells have a greater role: They actually activate the adaptive immune response. As a member of the adaptive immune system, dendritic cells serve as a bridge between the innate and adaptive systems.

Signaling activity initiated by the innate immune system’s inflammatory molecules stimulates a swift response by dendritic cells, which are already on patrol—on the hunt for invasive trouble.

Despite the chore of activating key players of the adaptive immune system, namely T cells—and, somewhat indirectly, triggering antibody-producing B cells—armies of DCs are inescapably doomed to death. Once their primary jobs of antigen presentation and stimulating the adaptive response are done, the cells are subject to programmed cell death, apoptosis, which leads to their demise. Simply put, nature ensured that armies of dendritic cells perish once their primary roles are complete. Fresh recruits replace the old cells in a renewal process that begins in the bone marrow.

Drs. Lukas Hatscher and Diana Dudziak of the Laboratory of Dendritic Cell Biology at University Hospital Erlangen, a division of Friedrich-Alexander University, led the team that uncovered a long-lasting subset of dendritic cells. They’ve identified them as human type 2 conventional dendritic cells.

Hatscher, Dudziak and their collaborators analyzed this dendritic population, obtaining them from a variety of sites—the blood, spleen and thymus. The organ-derived DCs used in the research were acquired from donated organs. Scientists compared their activity to human type 1 conventional dentritic cells. They found that longevity distinguished the type 2 population from the doomed type 1s.

Hiding in Plain Sight

The big surprise in the research was discovering that this elusive group of DCs had been hiding all along in plain sight. The challenge for the German team was elucidating why type 2 DCs stay active even though type 1s are programmed to die.

“Instead, these cells entered a ‘hyperactive’ state that enhanced the stimulation of certain T helper cell subsets,” Hatscher and Dudziak wrote in the journal Science Signaling, describing the dendritic cell population they discovered. “The findings suggest that conventional dendritic cells type 2 could be critical to the efficacy of vaccines and immunotherapies as well as for therapeutically controlling inflammation.”

The German team confirmed that type 2 DCs augment immune system activity by responding to inflammasome signaling. Chemically, inflammasomes are complex polymers and part of the innate immune system. Inflammasome signaling induces cytokines. The DC response to inflammasomes also occurs in vaccine immunity and the body’s ability to repel infections, Hatscher and Dudziak found.

Type 1 dendritic cells tend to undergo regulated cell death after inflammasomes activate. But the investigators found that automatic death wasn’t inevitable for type 2 DCs, which did not succumb after inflammasome activation. Type 2 DCs not only survived, but continued their role as a bridge between the innate and adaptive immune systems. The researchers suggest that these cells may be prime targets for approaches to treat inflammatory diseases or to boost the effects of vaccines and adjuvants.

“When conventional type 2 dendritic cells were stimulated with ligands that weakly activated the inflammasome, the DCs did not enter [programmed cell death], but instead secreted interleukin-12 family of cytokines [IL-12] and interleukin-1β [IL-1β]. These cytokines induced prominent T helper type 1 cells and T helper 17 responses,” the scientists wrote.

The discovery of how some dendritic cells survive and others are programmed to die was made by a large team of immunobiologists who represented more than a dozen leading research centers throughout Germany. Investigators described the signaling pathway that alerts these cells, and defined the biological role of dendritic sub-population. Scientists proved in their research that nuances of difference separate type 2 conventional differed from type 1s. “We found that the conventional type 2 dendritic cell subset is the major human DC subset,” the researchers concluded.

Dendritic cells, in general, act as sentinels by conducting surveillance in tissues. For instance, they can detect infection in the body by pinpointing “danger signals” linked with invading pathogenic agents. Dendritic cells regardless of type zero in on PAMPS—pathogen-associated molecular patterns—which are derived from microorganisms. One of the most notorious PAMPs is a potentially deadly bacterial component known as lipopolysaccharide, or LPS, which is found on the outer cell wall of gram-negative bacteria. Dendritics obtain antigens from the deadly invasive source—and the launch of the adaptive immune system assault on the infiltrator begins.

While the findings by Hatscher, Dudziak and their colleagues may prompt scientists worldwide to take stock of a broader role for these immune system constituents, it’s now clear that Germany has been in the vanguard of dendritic cell research for 153 years.

German pathologist Paul Langerhans, while still a medical student, was the first to describe DCs in skin cells. Although he mistakenly defined them as nerve cells, he is credited with bringing attention to bear on this hardworking cell population. (Langerhans is also famous for research involving the pancreas. An insulin-secreting cluster of cells in the pancreas is named after him: the islets of Langerhans).

Hatscher and Dudziak, meanwhile, report that their 21st-century discovery not only enhances overall knowledge about the , but paves the way for using this new knowledge in the fight against disease processes. “These findings not only define the human conventional type 2 dendritic cell subpopulation as a prime target for the treatment of inflammasome-dependent inflammatory diseases, but may also inform new approaches for adjuvant and vaccine development.”


Researchers discover regulatory pathway that blocks immune response against cancer


More information:
Lukas Hatscher et al. Select hyperactivating NLRP3 ligands enhance the TH1- and TH17-inducing potential of human type 2 conventional dendritic cells, Science Signaling (2021) DOI: 10.1126/scisignal.abe1757

© 2021 Science X Network

Citation:
153 years after discovery of the immune system’s dendritic cells, scientists uncover a new subset (2021, May 27)
retrieved 27 May 2021
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Engineered protein gives an energetic boost to cancer-fighting cells

Engineered protein gives an energetic boost to cancer-fighting cells

  • May 26, 2021

EPFL scientists have discovered that an engineered interleukin-10-Fc fusion protein can boost the effectiveness of exhausted T lymphocytes – our body’s immune cells for fighting cancer, by reprograming their metabolism.

One of the many treatment options available for cancer today is immunotherapy, which involves stimulating a patient’s immune system to produce lymphocytes (such as T cells) that go on to kill the tumor. Without immunotherapy, a patient’s lymphocytes are generally powerless against the disease. This form of treatment has shown to be effective, but it has a major drawback: it works on only 20-30% of patients. A majority of cancer pateints do not benefit from current cancer immunotherapies.

Teamwork

Researchers around the world are working hard to increase that percentage. At the Laboratory of Biomaterials for Immunoengineering led by Prof. Li Tang, within EPFL’s Institute of Bioengineering and School of Engineering, a group of scientists has led the joint efforts of six research labs at universities in different countries to study a new method for making immunotherapy more effective. The international team – comprised of 22 experts in fields ranging from biology and immunology to bioengineering and biocomputing – has just published their findings in Nature Immunology.

Professor Li Tang © 2021 EPFL

Boosting tired T cells

“The majority of cancer patients don’t respond to immunotherapy – that’s a major obstacle we need to overcome,” says Tang. “One explanation could be that the process of infiltrating a tumor and fighting cancer cells wears out the lymphocytes, making them too tired to halt the tumor’s progression. The scientific term for that is ‘T cell exhaustion’. The cells are not – or are no longer – responsive to immunotherapy.”

The scientists’ new method involves adding a newly engineered protein called interleukin-10-Fc fusion proteinto immunotherapy drugs. “Interleukin-10 can boost or suppress our immune system depending on the scenario. However, very little was known how exactly it interacts with tumor-infiltrating T cells until our research,” says Yuqing Xie a doctoral assistant at Tang’s lab. “But we seem to have found a new mechanism which could revitalize exhausted T cells.” Their tests indicate that interleukin-10-Fc acts as an energy booster, giving lymphocytes a second impetus so they can be reactivated and keep fighting tumors. Dr. Yugang Guo, a scientist at Tang’s lab, explains: “With this protein we are able to reprogram T cell metabolism and enhance their expansion and destructive capacity against cancer.”

A story of T cell exhaustion and reinvigoration © LBI/Xiaomeng Hu/2021 EPFL

Up to 90% healing rate

The method was tested on mice with unequivocal results – up to 90% of the diseased animals were able to defeat the cancer. “Interleukin-10-Fc appears to be highly effective. It works in synergy with adoptive T cell transfer immunotherapy, such as CAR-T therapy, or immune checkpoint inhibitors, leading to the eradication of established solid tumors and durable cures in a majority of treated mice. Our method seems to improve the existing immunotherapies against solid tumors, which are known to be difficult to be cured” says Tang. What’s more, no obvious side effects were observed during the tests, which bodes well for clinical trials in the future. The researchers Dr. Yugang Guo, Yuqing Xie and Prof. Li Tang have filed international patents of this new therapy and will soon be pushing it to clinical trials on patients.

Distinct from immune checkpoint blockades, interleukin-10-Fc (IL-10-Fc) directly expands terminally exhausted T cells and promotes their effector function through metabolic reprograming, leading to durable tumor control. © LBI/Yugang Guo/2021 EPFL

Bottleneck breakthrough

Among the tumor infiltrating T cells, a subset called ‘terminally exhausted CD8+ T cell’, does not respond to most existing immunotherapies including immune checkpoint blockades. It is known to be difficult to be reactivated. The study, led by Prof. Li Tang, shows that metabolic reprogramming of these cells through a molecule, called mitochondrial pyruvate carrier, is sufficient to restore the functionality of terminally exhausted CD8+ T cells for fighting cancer. This finding lays the foundation for further identification of metabolic stimulations that are needed for reinvigorating terminally exhausted CD8+ T cells, a current major bottleneck in the field of cancer immunotherapy.

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Immune cells imperfect at distinguishing between friend and foe, study suggests

  • May 25, 2021

When it comes to distinguishing a healthy cell from an infected one that needs to be destroyed, the immune system’s killer T cells sometimes make mistakes.

This discovery, described today in eLife, upends a long-held belief among scientists that T cells were nearly perfect at discriminating friend from foe. The results may point to new ways to treat autoimmune diseases that cause the immune system to attack the body, or lead to improvements in cutting-edge cancer treatments.

It is widely believed that T cells can discriminate perfectly between infected cells and healthy ones based on how tightly they are able to bind to molecules called antigens on the surface of each. They bind tightly to antigens derived from viruses or bacteria, but less tightly to our own antigens on normal cells. But recent studies by scientists looking at autoimmune diseases suggest that T cells can attack otherwise normal cells if they express unusually large numbers of our own antigens, even though these bind only weakly.

“We set out to resolve this discrepancy between the idea that T cells are near perfect at discriminating between healthy and infected cells based on the antigen binding strength, and clinical results that suggests otherwise,” says co-first author Johannes Pettmann, a D.Phil student at the Sir William Dunn School of Pathology and Radcliffe Department of Medicine, University of Oxford, UK. “We did this by very precisely measuring the binding strength of different antigens.”

The team measured exactly how tightly receptors on T cells bind to a large number of different antigens, and then measured how T cells from healthy humans responded to cells loaded with different amounts of these antigens. “Our methods, combined with computer modelling, showed that the T cell’s receptors were better at discrimination compared to other types of receptors,” says co-first author Anna Huhn, also a D.Phil student at the Sir William Dunn School of Pathology, University of Oxford. “But they weren’t perfect – their receptors compelled T cells to respond even to antigens that showed only weak binding.”

“This finding completely changes how we view T cells,” adds Enas Abu-Shah, Postdoctoral Fellow at the Kennedy Institute and the Sir William Dunn School of Pathology, University of Oxford, and also a co-first author of the study. “Instead of thinking of them as near-perfect discriminators of the antigen binding strength, we now know that they can respond to normal cells that simply have more of our own weakly binding antigens.”

The authors say that technical issues with measuring the strength of T cell receptor binding in previous studies likely led to the mistaken conclusion that T cells are perfect discriminators, highlighting the importance of using more precise measurements.

“Our work suggests that T cells might begin to attack healthy cells if those cells produce abnormally high numbers of antigens,” says senior author Omer Dushek, Associate Professor at the Sir William Dunn School of Pathology, University of Oxford, and a Senior Research Fellow in Basic Biomedical Sciences at the Wellcome Trust, UK. “This contributes to a major paradigm shift in how we think about autoimmunity, because instead of focusing on defects in how T cells discriminate between antigens, it suggests that abnormally high levels of our own antigens may be responsible for the mistaken autoimmune T-cell response. On the other hand, this ability could be helpful to kill cancer cells that mutate to express abnormally high levels of our antigens.”

Dushek adds that the work also opens up new avenues of research to improve the discrimination abilities of T cells, which could be helpful to reduce the autoimmune side-effects of many T-cell-based therapies without reducing the ability of these cells to kill cancer cells.

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