A team of Stanford scientists led by Polly Fordyce, an Institute Scholar at Sarafan ChEM-H, has developed a new method to faster and more accurately predict which antigens will lead to a strong immune response. Their approach, which was reported in Nature Methods on Sept. 5, could help scientists develop more effective cancer immunotherapies.

T cells, a class of immune cells, crawl along and squish past other cells as they patrol the body, using T cell receptors to molecularly read peptides, or short pieces of proteins — which are cradled within larger proteins called major histocompatibility complexes (pMHCs) that project from cell surfaces. Healthy host cells display an array of pMHCs that do not trigger an immune response, but once T cells recognize disease-indicating peptides, they become activated to find and kill cells bearing these foreign signatures. Understanding how T cells sensitively distinguish these antigenic peptides from host peptides to avoid mistakenly killing host cells has long been a mystery.

“A T cell can detect a single antigenic peptide amongst a sea of 10,000 or 100,000 non-antigenic peptides being displayed on cell surfaces,” said Fordyce, assistant professor of bioengineering and of genetics.

The key to selectivity is in the T cell crawl. T cells’ sliding puts stress on the bonds between receptors and peptides, and in most cases, that extra stress is enough to break that bond. But sometimes, it has the opposite effect. Chris Garcia, co-author of the study and professor of molecular and cellular physiology and of structural biology, and others had already shown that the most antigenic peptides are those whose interactions with T cell receptors grow stronger in response to sliding.

“It’s kind of like a Chinese finger trap,” said Fordyce. “When you pull a bit at the receptor-antigen interaction, the binding actually lasts longer.”

Cellular mimicry

Identifying the best antigen-receptor pairs requires simultaneously applying that sliding, or shear, force between a peptide and a T cell and measuring T cell activation, ideally thousands of times to get repeatable data for many possible peptide/T cell receptor pairs. But existing methods are time-intensive and can result in measuring only one peptide with hundreds of T cells in a day.

The study’s first author, postdoctoral scholar Yinnian Feng, developed a trick that allows the team to measure 20 unique peptides interacting with thousands of T cells in less than five hours.

To make a simplified system that mimics cells with dangling peptides, they constructed small spherical beads from a material that expands upon heating and attached a few molecules of a given peptide-studded pMHC to their surfaces. After depositing a T cell atop each bead and waiting long enough for receptors to bind to the peptides, they then very slightly heated the bead. The bead’s expansion increases the distance between tether points, and the corresponding stretching of the T cell mimics the force it would experience sliding along cells in the body. After exerting that force, the team then measured how active the T cells were.

They could do hundreds of individual experiments in parallel by using beads that are each labeled with a unique color, making it possible to track multiple different pMHCs. They took two sets of pictures tiling across each slide after each run: one set that tells them which pMHC a given bead is displaying and another that tells them how active each T cell atop that bead is. Cross-referencing those images tells them which antigens led to the strongest T cell responses.

In this demonstration of their platform, the team showed, with 21 unique peptides, that their results confirmed known activating and non-activating peptides for one T cell receptor and uncovered a previously unknown antigen that induced a strong T cell response. Working with the Garcia lab, they have also already begun to address a challenge in immunotherapy: the T cell receptors that form the highest affinity interactions with antigens in the lab are often also activated by non-antigenic peptides in the body, a dangerous side effect that leads to the killing of healthy cells. Using their technology, the team characterized T cell receptors engineered to specifically recognize tumor antigens without off-target reactivity. In future work, they plan to build libraries of over 1,000 peptides to uncover novel antigens.

They hope that this approach, which is quick and requires few cells, or an optimized form of it could one day be used to improve personalized immunotherapies.

“This platform can help improve efforts to engineer T cells that specifically target cancer cells, as well as determine which antigens are capable of potently activating a patient’s own T cells to more effectively target cancer cells,” said Fordyce.

Fordyce is a member of Stanford Bio-X, SPARK, and the Wu Tsai Neurosciences Institute, and is a Chan Zuckerberg Biohub investigator. Garcia is a member of Stanford Bio-X, the Stanford Cancer Institute, the Wu Tsai Neurosciences Institute, and a Howard Hughes Medical Institute investigator.

Xiang Zhao and Adam K. White are also authors of the paper.

The work was funded by a Stanford Bio-X Interdisciplinary Initiatives seed grant and the National Institutes of Health.

COPD, a lung disease that obstructs the airways and leads to coughing, wheezing, and shortness of breath, affects about 15 million Americans. However, millions of others who smoke or used to smoke and have some symptoms of COPD have also been prescribed bronchodilators.

“We’ve assumed these medications worked in patients who don’t meet lung function criteria for COPD, but we never checked,” said MeiLan K. Han, M.D., a principal investigator and first author of the study. “We now know these existing medications don’t work for these patients.”

The findings of the study, which was funded by the National Heart, Lung, and Blood Institute (NHLBI), were published in the New England Journal of Medicine and simultaneously presented at the European Respiratory Society International Congress.

According to scientists, the implications are significant. First, they show the importance of diagnosing lung conditions through spirometry, a lung function test Han noted is underutilized in clinical practice. Second, they show the need for new, effective therapies for patients without COPD.

Inhalers have long been the primary go-to treatment for these patients, she explained, because doctors either assume a patient has COPD, or if they don’t, that their smoking-related symptoms could be helped by the inhalers. But while tobacco smoking causes a large spectrum of lung damage, the study showed bronchodilator therapy only helps patients with enough lung damage that would result in abnormal spirometry readings.

In the 12-week, randomized, double-blinded study, which was part of the Redefining Therapy in Early COPD for the Pulmonary Trials Cooperative(RETHINC), researchers enrolled 535 adults with symptoms of COPD, ages 40-80, at one of 20 U.S. medical centers. Twice each day, study participants used an inhaler that contained either medication or a placebo.

By the end of the trial, some adults in the medication (intervention) and placebo (control) groups saw slight respiratory improvements — this could mean they coughed less, produced less phlegm, or felt less winded — which was assessed through the St. George’s Respiratory Questionnaire. However, the researchers found no significant differences between those receiving medication or placebo. They reported 56% (128 of 227) of participants who received the medication saw respiratory symptom improvements, compared to 59% (144 of 244) of those who took the placebo.

According to Han, these data underscore why we can’t continue to do what we have been doing, which is not doing spirometry and just treating patients with the same COPD medications and expect that we’re going to see improvement.

Antonello Punturieri, M.D., Ph.D., program director of NHLBI’s Chronic Obstructive Pulmonary Disease/Environment Program, said spirometry testing should be used for any patient who shows signs of COPD, airflow obstruction, or who has a history of cigarette smoking. Though spirometry readings are used during about one-third of medical visits related to COPD, roughly half of patients who would meet criteria for COPD go undiagnosed.

Helping patients quit smoking is a primary way to prevent COPD or COPD-like symptoms, the study noted. More than 30 million adults smoke, according to the Centers for Disease Control and Prevention, and many who are not diagnosed with COPD share symptoms. About one in four current or former smokers without COPD have reported having shortness of breath. In addition to encouraging smoking cessation, doctors can help patients who do not meet lung-function criteria of COPD by working with them to address any other underlying issues, such as overweight and obesity, heart failure, or other lung issues.

“In the meantime, research should be focused on finding new treatments for them,” Han explained. “The next question is, can we develop more targeted therapies for these patients who are on the milder end of the spectrum?”

“Because cough and mucus production show up prominently among these patients, we believe therapies that target mucus production in the airways may be effective,” said Prescott G. Woodruff, M.D., a principal investigator and senior author of the study.

Some of these therapies are already in development, and data from other studies may offer insight into the biological causes of excessive airway mucus. Those clues could help researchers identify additional therapies.

Working with a select number of London schools, researchers from Surrey’s Global Centre for Clean Air Research (GCARE) investigated whether putting up a green screen along the perimeter fence of a school, installing air purifiers in classrooms, and organising school street initiatives during pick-up and drop-off hours, improved air quality of classrooms and playgrounds. These initiatives were funded by Impact on Urban Health.

The researchers found that air purifiers in classrooms reduced indoor pollution concentrations by up to 57%, and the School Streets initiative, which stops motor vehicles driving past schools at the start and end of school days, reduced particle concentrations by up to 36%. Green screens at the school boundary reduced some of the most dangerous outdoor particle levels coming from roads by up to 44%, depending on wind conditions.

Prashant Kumar, founding Director of the Global Centre for Clean Air Research (GCARE) at the University of Surrey, said:

“Everybody, especially our children, deserves to live and work where the air is as clean and safe as possible. Unfortunately, the reality is far from ideal, with many of our schools unwittingly exposing children to harmful pollutants. The problem is particularly bad at schools near busy roads.

“Our research offers hope to many who care about this issue, as the results show that taking reasonable action can make a positive difference.”

Ten million students worldwide spend 30% of their daily lives at school, with 70% of this time being spent indoors. Currently, 7,000 UK schools breach the World Health Organization’s air quality limits, leaving children vulnerable to respiratory diseases, affected lung and brain health, behavioural problems, and increased risk of cancer.

Kate Langford, Programme Director of the Health Effects of Air pollution programme at Impact on Urban Health, funders of the research, said:

“Every child has the right to learn in an environment that keeps them safe and healthy. But, every day, children are exposed to dangerously high levels of air pollution in and around schools.

“Our partnership with Arup, Global Action Plan and the University of Surrey has shown there are practical ways that we can protect children in and around schools and can help guide schools to implement these solutions.

“These measures now need to be combined with efforts from local authorities at regional and national levels to improve air quality and create healthier places for children to live, learn and play.”

Larissa Lockwood, Director of Clean Air at Global Action Plan, said:

“Schools should be safe places of learning, not places where students are at risk of health hazards. There is no safe level of air pollution, but children are particularly vulnerable to its impacts including the development of organs and their ability to learn. Services like the London Schools Pollution Helpdesk ensure that schools have access to advice on what they can do to reduce exposure to air pollution, including the measures tested in this research. But this needs to be rolled out nationally — all children must be protected from the health effects of air pollution in their everyday lives.”

Professor Prashant Kumar concluded:

“My simple plea to decision-makers in the UK is this: simple actions speak louder than words. By giving every school resources to implement one of the measures detailed in our research, they could make a world of difference to tens of thousands of children in this country.”

The study was co-designed by Global Action Plan and Arup and supported by Impact on Urban Health.

The research was published in the journal Atmospheric Environment. Schools looking to implement changes can use a toolkit for guidance and should seek advice from an air quality specialist.

Now, a team of researchers has investigated how the narrow temperature ranges of a tropical climate impact the incidence of a specific type of myocardial infarction (the medical term for a heart attack) in Singapore. The researchers say their findings, published in the journal Science of the Total Environment, could have health policy implications for populations within cosmopolitan cities in the tropics.

“Using 10 years of nationally collected data, we found strong evidence that a drop of 1°C in ambient temperature increased the risk of a type of acute myocardial infarction in the population by 12 per cent,” said co-senior author Professor Marcus Ong, Director of the Health Services & Systems Research Programme and the Pre-hospital & Emergency Research Centre (PERC) at Duke-NUS Medical School.

“Furthermore, people aged 65 and above appeared to be about 20 per cent more vulnerable to cooler temperatures compared to younger people,” added Prof Ong, who is also Senior Consultant at the Department of Emergency Medicine at Singapore General Hospital (SGH).

The study, which was conducted in collaboration with Singapore’s National Environment Agency (NEA), analysed daily patient records from the Singapore Myocardial Infarction Registry. The researchers were specifically looking for people who experienced non-ST-segment elevation myocardial infarction (NSTEMI). This is a type of acute heart attack that happens when a blood vessel feeding the heart becomes partially blocked. When doctors examine the patient’s electrocardiogram (ECG) results, they don’t find the easily identifiable ST elevation that signifies another type of heart attack, STEMI, which occurs when the coronary artery is completely blocked. Since the 1980s, the incidence of NSTEMI has risen while that of STEMI has declined.

The researchers were able to collect 60,643 reports of NSTEMI between 2009 and 2018. They then statistically analysed how the onset of NSTEMI in these patients correlated with local meteorological data obtained from weather stations across Singapore, including mean temperature and rainfall.

Cooler ambient temperatures were independently associated with an increased risk of NSTEMI up to 10 days after a temperature drop. There were no gender differences relating to the effects of warmer or cooler temperatures on NSTEMI risk. Nor were changes in rainfall associated with an increased risk.

“Our study found that even in a relatively warm part of the world, cooler ambient temperatures increased the risk of heart attacks,” said Dr Andrew Ho, one of the study’s first authors, who is an Assistant Professor with PERC and an Associate Consultant with SGH’s Department of Emergency Medicine. “This improves our understanding that deviations from the temperature that one is used to can lead to harmful bodily stress. Consistent with our previous studies that showed that the elderly were more susceptible to environmental stressors including air pollution, we found some evidence that this group of individuals were at greater risk of heart attacks at cooler temperatures.”

“There are several individual-level risk factors for cardiovascular disease, but none are as widely experienced as weather patterns,” said Dr Joel Aik, an environmental epidemiologist and co-senior author of the study from NEA, who is also an Adjunct Assistant Professor with PERC. “Daily weather variations have the capacity to trigger cardiovascular disease events in at-risk individuals, with particular implications for Singapore’s ageing population. In the context of climate change, these findings highlight a risk factor of substantial public health concern.”

Further research over a longer period is needed to confirm the results. The team also recommends research that helps to identify the biological pathways involved in increased vulnerability of the elderly to cold-related NSTEMI in the tropics.

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Materials provided by Duke-NUS Medical School. Note: Content may be edited for style and length.

Lead author Theresa Andrasfay, a postdoctoral scholar at the University of Southern California Leonard Davis School of Gerontology, and coauthor Noreen Goldman at the Princeton School of Public and International Affairs first examined the pandemic’s effect on U.S. life expectancy in October 2020. Their initial study, published in Proceedings of the National Academy of Sciences in January 2021, showed that 2020 presented the largest single-year decline in life expectancy in at least 40 years and the lowest life expectancy estimated since 2003.

The updated analysis, published in PLOS ONE, indicates that U.S. life expectancy at birth decreased by 2.2 years from 78.8 in 2019 to 76.6 in 2021. The estimated decrease in life expectancy for 2021 is 0.6 years larger than the decrease observed in 2020, Andrasfay said.

“Despite the availability of effective vaccines, life expectancy continued to decline in 2021. Part of this is due to the large number of COVID-19 deaths that occurred in the beginning of 2021, before many individuals were eligible for vaccination,” she said. “But even once all adults became eligible for vaccination, many chose not to be vaccinated and even vaccinated individuals were not completely protected against the highly transmissible Delta and Omicron variants.”

The study highlighted that significant racial disparities in loss of lifespan have endured throughout the pandemic. Between 2019 and 2021, non-Latino whites lost 2 years on average, while non-Latino Blacks lost 3.5 years and Latinos lost 3.7 years of life expectancy. As noted in Andrasfay and Goldman’s previous analyses, Black and Latino Americans have experienced a disproportionate burden of coronavirus infections and deaths, reflecting persistent structural inequalities that heighten risk of exposure to and death from COVID-19. Goldman noted that “although Whites experienced a larger drop in life expectancy between 2020 and 2021 than the Black and Latino populations, resulting in a very modest reduction in racial and ethnic differences, the disparities in life expectancy loss since the start of the pandemic remain regrettably and unacceptably large.”

Although COVID-19 is the primary cause of continued life expectancy reductions in 2021, “increases in other causes of death relative to pre-pandemic levels contribute to these life expectancy declines,” the authors wrote. The pandemic appears to have played a role in the increase of drug overdose deaths in 2020 and 2021, and increased mortality from conditions such as heart disease or diabetes may be attributable to complications of Covid-19 infections and/or health care shortages and delays.

This week the CDC also released provisional estimates of life expectancy in 2021. “We did not have access to the same level of detailed data as the CDC, so we arrived at slightly different life expectancy estimates,” Andrasfay said. “Despite these differences, our results are largely in agreement in that we find continued life expectancy reductions in 2021 and persistent racial and ethnic disparities.”

“COVID-19 mortality has been lower in the first half of 2022 compared to 2021, so if there is a successful booster campaign in the fall and the dominant strains have lower fatality rates than previous variants, it is possible that 2022 life expectancy may improve relative to 2021, though it is unlikely to return to levels seen prior to 2020,” she added. “However, what happens with 2022 life expectancy will ultimately depend on this coming fall and winter.”

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Materials provided by University of Southern California. Original written by Beth Newcomb. Note: Content may be edited for style and length.