Research provides new insight into fundamental workings of the immune system in response to therapy to treat skin cance

New research led by the University of Birmingham suggests that skin cancer patients could have a better prognosis if their T cells send messages from five specific genes in their immune response to drugs given to treat the disease.

The research, carried out in mice, cells in the laboratory, and using publicly available data from patients with advanced melanoma before and after treatment with Nivolumab therapy, is published in Immunity.                         

T cells are white blood cells that protect the body from harm from viruses, bacteria, and cancer cells, and explore their environments by using their T cell receptor (TCR) to recognise fragments, called antigens, of microbes or damaged cancer cells.

The TCR controls the behaviour of the T cell and can send messages to the T cells’ command centre to kick-start an immune response. This process is important for vaccine research and treatment of autoimmune conditions, but is particularly of interest for cancer treatments to improve the anti-tumour function of T cells.

The researchers carried out the study to better understand how the amount of antigen controls how the TCR sends messages to the T cells’ command centre, and how this affects the type of immune response.

They wanted to explore how antigen amounts control the expression of so-called ‘immune checkpoints’ that act as brakes on immune responses. It is these immune brakes, such as one called PD1, that are the target of drugs that seek to increase the immune response in cancer immunotherapy.

Lead author Dr David Bending, of the University of Birmingham’s Institute of Immunology and Immunotherapy, explained:  “Through our research we discovered that the amount of antigen determined how many immune checkpoints or immune brakes a T cell had on its cell surface.”

“When we exposed T cells to the highest amounts of antigen, they stopped sending signals to their command centre, and this was because they had increased the number of immune brakes, which shut down the messengers. This made these T cells unable to respond to antigens for a period.”

By blocking one of the immune brakes, called PD1, the researchers were able to re-awaken some of these ‘unresponsive’ T cells. They found that these re-awakened T cells not only started sending messages to their command centres, but the messages they sent were louder and clearer.

“The response from the command centre was that the T cells started to increase the number of messages from five specific genes,” added Dr Bending.

“By looking for the messages from these five genes, we were able to show that these stronger and louder messages were increased in melanoma patients who survived for longer on drugs that block the immune brake PD1. We think that this means that those cancer patients whose immune cells can send messages from these five genes in response to drugs that target PD1, a good outcome is far more likely.”

The researchers said their finding shows that the immune system likely requires an optimal level of stimulation to mount the most effective immune response in skin cancer patients.

Dr Bending added: “Our research gives us interesting insight into fundamental workings of the immune system. It suggests that both the amount of antigen around a T cell and also the number of immune brakes the T cells have at their surface are very important in controlling immune responses. Furthermore, we have shown that we can alter the balance of the immune response through stopping some of these immune brakes, which results in a stronger T cell response.”

The study has generated a new potential readout to monitor patients on drugs targeting PD1 in cancer. It also may be useful for exploring the potential of combinations of drugs that target multiple immune checkpoints to try to further re-awaken T cells in cancer patients.

Therapy using dual immune system cells effectively controls neuroblastoma

A newly developed immunotherapy that simultaneously uses modified immune-fighting cells to home in on and attack two antigens, or foreign substances, on cancer cells was highly effective in mice implanted with human neuroblastoma tissue, report researchers from the UNC Lineberger Comprehensive Cancer Center and the UNC School of Medicine.

The dual targeting restricted regrowth of the tumour as well as prevented the neuroblastoma cells from evading the attacking immune cells.

The research findings are published in Nature Cancer.

Neuroblastoma is a cancer of immature nerve cells and occurs mainly in children younger than six years of age. The tumours are typically found on top of adrenal glands but can also develop in the abdomen, chest, neck, pelvis, and bone. Approximately 500 to 1,000 cases are diagnosed annually in the United States.

“Tumour cells are characterised by a mixed expression of antigens, and we engineered dual immune-system T cells to maximise their capacity to prevent tumours from evading detection by the immune system,” said Hongwei Du, PhD, a postdoctoral fellow at UNC School of Medicine.

“Furthermore, the modified T cells were also able to receive important signals, which is somewhat unique as there have been many challenges in getting certain types of immunotherapies to overcome the unfriendly tumour environment found in solid tumours.”

The researchers utilised CAR-T cell (chimeric antigen receptor-T cell) immunotherapy, which involves harvesting immune-system T cells from a patient and genetically re-engineering them in the lab to recognise targets on the surface of cancer cells when they are re-infused into patients.

Specifically, the scientists coupled the recognition of two antigens expressed by the tumour cells with the combination of two key co-stimulatory molecules: CD28, a protein expressed on T cells after early activation, and 4-1BB, an important co-stimulatory protein that is involved in T-cell survival and memory formation.

Both CD28 and 4-1BB have been shown to be equally effective in clinical studies in patients with blood-borne cancers when used individually. However, the combination of CD28 and 4-1BB co-stimulation appears to be critical in solid tumours. Research efforts by Du resulted in ways to deliver both signals efficiently.

The scientists first looked at neuroblastoma cells in the laboratory to see how they responded to a combined immune cell attack. Given the positive results of the lab studies, the researchers then looked at mice implanted with neuroblastoma to see how they would respond to co-stimulation by CD28 and 4-1BB modified T cells.

Indeed, the co-stimulatory cells were very effective in reducing cancer in mice bearing large numbers of neuroblastoma tumours.

“We know that certain CAR-T therapies are safe for patients with solid tumours, but so far treatments have not led to the degree of tumour regression we would like to see,” said Gianpietro Dotti, MD, professor in the UNC School of Medicine Department of Microbiology and Immunology and co-leader of the Immunology Program at UNC Lineberger.

“We ultimately designed a strategy that simultaneously addresses the most challenging tasks in solid tumours, such as generating CAR-T cells that rapidly eliminate the tumour and persist in controlling tumour growth. Furthermore, our system prevents tumour recurrence.”

If this therapeutic approach is as promising in people as it has been in mice, the researchers said targeting three, four or more antigens expressed by tumour cells could be even more effective.

They will proceed with caution as over-stimulation could exponentially increase side-effects. To counter this, the researchers can use a ‘safety switch’ technology that Dotti, Barbara Savoldo, MD, PhD, professor of paediatrics and assistant director of the UNC Lineberger Immunotherapy Program, and others developed to regulate the level of CAR-T generated stimulation.

“We are currently implementing clinical studies to look at several potential single targets,” said Dotti.

“If these studies prove that the therapies are safe, we’ll then progress to the next logical step, which is looking to see if our therapy is effective against a combination of targets.”

In rare cases, immune system fails despite HIV suppression

Antiretroviral therapy (ART) is usually very effective at suppressing HIV in the body, allowing a person’s immune system to recover by preventing the virus from destroying CD4+ T cells(link is external).

Colorized scanning electron micrograph of a T lymphocyte.NIAID

Scientists have now identified a rare, paradoxical response to ART known as extreme immune decline, or EXID. Five individuals evaluated at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, experienced a significant decline in CD4+ T cell levels despite suppression of HIV below detectable levels for more than three years, according to a report published online today in JCI Insight.  

The research team was led by Irini Sereti, M.D., chief of the HIV Pathogenesis Section in NIAID’s Laboratory of Immunoregulation, and Andrea Lisco, M.D., Ph.D.

The NIAID researchers found that the immune systems of people with EXID fared even worse than those of another subset of individuals defined as immunological-non-responders, or INRs, who respond inadequately to ART.  INR participants consistently taking ART for four years had CD4+ T cell counts that increased on average by 193 cells per microliter (µL) of blood.  Participants who responded normally to ART increased their CD4+ T cell count by more than twice that amount. In contrast, the five participants with EXID experienced an average decline of 157 CD4+ T cells/µL while consistently maintaining viral suppression on ART.

According to the NIAID team, there seems to be no single cause of EXID among the five individuals studied. Their analyses revealed that genes influencing immune cell activity and autoimmunity—the immune system attacking a body’s own healthy tissue—may play a role. Specifically, two of the individuals with EXID produced antibodies that attacked their own T cells, while two others had overactive cellular immune responses that lead to increased inflammation. All five participants with EXID had HIV strains other than clade B HIV (the most common strain circulating in North America and Europe), indicating that certain combinations of an individual’s genes and the HIV strain may be associated with EXID. While EXID is likely an extremely rare response to ART, the researchers indicate that studying this phenomenon may further illuminate CD4+ T cell reconstitution and inflammation in HIV disease and suggest possible treatment strategies for INRs and individuals with EXID.

NIH study implicates hyperactive immune system in aging brain disorders

Results suggest a breakdown in brain cell waste system triggers a destructive immune reaction.

In a study of flies, NIH scientists showed how the immune system may be a culprit in the damage caused by aging brain disorders.Giniger Lab, NIH/NINDS

In a study of fruit flies, NIH scientists suggested that the body’s immune system may play a critical role in the damage caused by aging brain disorders.

The results are based on experiments in which the researchers altered the activity of Cdk5, a gene that preclinical studies have suggested is important for early brain development and may be involved in neurodegenerative diseases, such as ALS, Alzheimer’s and Parkinson’s disease. 

Previously, they found that altering Cdk5 sped up the genetic aging process, causing the flies to die earlier than normal and have problems with walking or flying late in life and greater signs of neurodegenerative brain damage.

In this study, published in Cell Reports, they suggested that altering Cdk5 resulted in the death of dopamine releasing neurons, especially in the brains of older flies. Typically, Parkinson’s disease damages the same types of cells in humans.

Further experiments in flies suggested the neuron loss happened because altering Cdk5 slowed autophagy, or a cell’s waste disposal system that rids the body of damaged cells in a contained, controlled fashion, which in turn triggered the immune system to attack the animal’s own neurons. This immune system attack is a much “messier” and more diffuse process than autophagy. 

Genetically restoring the waste system or blocking the immune system’s responses prevented the reduction in dopamine neurons caused by altering Cdk5. The authors concluded that this chain reaction in which a breakdown in autophagy triggers a widely destructive immune reaction may occur in human brain during several neurodegenerative disorders and that researchers may want to look to these systems for new treatment targets and strategies.

Who

Edward Giniger, Ph.D., senior scientist, NIH’s National Institute of Neurological Disorders and Stroke (NINDS)

Article

Shukla et al. Hyperactive innate immunity causes degeneration of dopamine neurons upon altering activity of Cdk5, January 2, 2019, Cell Reports

This study was supported by the Intramural Research Program at the NINDS (NS003106).

Multi-Disease Health Fairs, Universal “Test and Treat” Help East African Communities Achieve HIV Benchmarks

PEPFAR- and NIH-Supported Study Results Support Patient-Centered Approach to Care Delivery

People living with HIV in rural East African communities that hosted annual community health campaigns initiated antiretroviral therapy (ART) earlier and had higher levels of overall survival and viral suppression than communities receiving standard HIV care, according to study data presented today at a press conference at the 22nd International AIDS Conference (AIDS 2018) in Amsterdam.

A SEARCH health educator in Kisoro, Uganda, sings about the need to be tested for HIV and start ART.

Communities with annual multi-disease health fairs, which delivered patient-centered, streamlined HIV care, also had fewer cases of tuberculosis (TB), better control of hypertension and approximately 30 percent fewer new HIV cases during the last year of the study compared to the first year.

The study, known as Sustainable East Africa Research in Community Health (SEARCH), is supported by the President’s Emergency Plan for AIDS Relief (PEPFAR) and the National Institutes of Health (NIH).

SEARCH investigators randomly assigned 32 rural communities in Uganda and Kenya to receive either a multi-faceted intervention that integrated universal HIV testing and treatment into annual health screenings for multiple conditions or standard HIV care at HIV clinics, which consisted of baseline community-wide HIV testing and treatment with ART in accordance with national guidelines. In 2015, while the study was taking place, national guidelines in Uganda and Kenya shifted from a recommendation that individuals begin ART when CD4+ T cell levels—an indicator of immune system health—dipped below a certain threshold to a recommendation that all individuals living with HIV begin ART at the time of diagnosis.

In communities randomized to receive the intervention, the SEARCH team held annual community health campaigns, which began with a census and then engaged community members through two-week health fairs. Participants received health education; screenings for HIV hypertension, diabetes, and TB; and prompt care for any health conditions detected, including providing immediate ART for those who tested positive for HIV.

At the end of the three-year study, rates of deaths from any cause among people living with HIV in the intervention communities were 21 percent lower than in communities receiving standard care. People living with HIV in communities that received the intervention also experienced 59 percent fewer new TB cases compared with the standard care communities. TB, a bacterial infection that affects the lungs, is a leading cause of death among people living with HIV across the globe and is particularly endemic in East Africa.

Prior to the study, investigators found that nearly half of individuals living with HIV in the 32 rural communities in Uganda and Kenya were virally suppressed—consistent use of daily ART had reduced their HIV blood levels to undetectable by standard tests. HIV suppression both benefits the health of those living with HIV and prevents sexual transmission(link is external) of the virus. At the end of the three-year study, 80 percent of people living with HIV in communities randomized to the intervention were virally suppressed compared to 68 percent in communities that received standard HIV care.

“We know that the ability of antiretroviral therapy to suppress HIV to undetectable levels is not only life-saving for individuals, but also prevents sexual transmission of the virus,” said Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases, part of NIH. “Innovative implementation of antiretroviral therapy through community health initiatives may be one way to save lives and change the trajectories of even the most ingrained epidemics.”

The SEARCH study outcomes exceeded international HIV testing and treatment goals set by UNAIDS, which call for 90 percent of people living with HIV to be diagnosed, 90 percent of those diagnosed to be on ART, and 90 percent of those in treatment to be virally suppressed by 2020. If met, the 90-90-90 targets would result in 73 percent of people living with HIV being virally suppressed. At the start of the study, the SEARCH team tested about 90 percent of the population in communities set to receive either the intervention or standard care. Through repeated annual testing in intervention communities, more than 95 percent of the population received an HIV test. Those diagnosed through community health campaigns were more likely to start ART, and viral suppression increased dramatically among individuals taking ART in all communities. In intervention communities, population-level viral suppression was 80 percent, surpassing the 90-90-90 target of 73 percent. Standard care communities approached the target with 68 percent of community members living with HIV virally suppressed. The reduction in HIV infections over the course of the study was similar between intervention and standard care communities.

“Our team hypothesized that partnering with communities to deliver patient-centered care for a range of common diseases, including but not exclusively HIV, would reduce new HIV infections and improve community health,” said Diane Havlir, M.D., principal investigator of SEARCH, at the University of California, San Francisco.

Investigators found that annual community health campaigns and streamlined care delivery also had a positive impact on the burden of diseases other than HIV. Patient-centered health care in the intervention communities led to better control of hypertension and diabetes. Investigators observed 16 percent fewer cases of uncontrolled hypertension in intervention communities compared with standard care communities, where uncontrolled hypertension was common.

While men and youth have participated at lower rates in HIV testing and treatment programs in Sub-Saharan Africa, the SEARCH model resulted in 74 percent of men living with HIV in intervention communities achieving viral suppression by the end of the study. However, youth between the ages of 15 and 24 living with HIV were nearly 20 percent less likely to be virally suppressed compared with community members over age 24. Investigators also found that about two thirds of all study participants who acquired HIV during the study period were women, but that in Western Uganda, a higher proportion of people who acquired HIV during the study were young, single men of low social and economic status.

SEARCH is led by Dr. Havlir and by co-principal investigators Moses Kamya, M.B.Ch.B., Ph.D., at Makerere University in Uganda, and Maya Petersen, M.D., Ph.D., at the University of California, Berkeley.

NIH scientists find microbes on the skin of mice promote tissue healing, immunity

Insights may inform wound management techniques.

Immunofluorescent image of immune cells surrounding a skin wound, enriched in the beneficial bacteria S. epidermidis. NIAID

Beneficial bacteria(link is external) on the skin of lab mice work with the animals’ immune systems to defend against disease-causing microbes and accelerate wound healing, according to new research from scientists at the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health. Researchers say untangling similar mechanisms in humans may improve approaches to managing skin wounds and treating other damaged tissues. The study was published online today in Cell.

Like humans and other mammals, mice are inhabited by large, diverse microbial populations collectively called the microbiome. While the microbiome is believed to have many beneficial functions across several organ systems, little is known about how the immune system responds to these harmless bacteria.

To investigate, NIAID scientists led by Yasmine Belkaid, Ph.D., chief of the Mucosal Immunology Section of NIAID’s Laboratory of Parasitic Diseases, observed the reaction of mouse immune cells to Staphylococcus epidermidis, a bacterium regularly found on human skin that does not normally cause disease. To their surprise, immune cells recognized S. epidermidis using evolutionarily ancient molecules called non-classical MHC molecules, which led to the production of unusual T cells(link is external) with genes associated with tissue healing and antimicrobial defense. In contrast, immune cells recognize disease-causing bacteria with classical MHC molecules, which lead to the production of T cells that stoke inflammation.

 Researchers then took skin biopsies from two groups of mice—one group that had been colonized by S. epidermidis and another that had not. Over five days, the group that had been exposed to the beneficial bacteria experienced more tissue repair at the wound site and less evidence of inflammation. Dr. Belkaid’s team plans to next probe whether non-classical MHC molecules recognize friendly microbes on the skin of other mammals, including humans, and similarly benefit tissue repair. Eventually, mimicking the processes initiated by the microbiome may allow clinicians to accelerate wound healing and prevent dangerous infections, the researchers note.

Yasmine Belkaid, Ph.D., Mucosal Immunology Section Chief in NIAID’s Laboratory of Parasitic Diseases and study co-author.