With a goal of understanding and addressing immunotherapy’s limitations, researchers at Washington University School of Medicine in St Louis have found that the immune system can be its own worst enemy in the fight against cancer. In a new study in mice, a subset of immune cells — type 1 regulatory T cells, or Tr1 cells — did its normal job of preventing the immune system from overreacting but did so while inadvertently restraining immunotherapy’s cancer-fighting power.

“Tr1 cells were found to be a heretofore unrecognized obstacle to immunotherapy’s effectiveness against cancer,” said senior author Robert D. Schreiber, PhD, the Andrew M. and Jane M. Bursky Distinguished Professor in the Department of Pathology & Immunology, and director of the Bursky Center for Human Immunology & Immunotherapy at Washington University School of Medicine. “By removing or circumventing that barrier in mice, we successfully reenergized the immune system’s cancer-fighting cells and uncovered an opportunity to expand the benefits of immunotherapy for more cancer patients.”

The study is available in Nature.

Cancer vaccines represent a new approach to personalize cancer immunotherapy. Aimed at the mutant proteins specific to a patient’s tumor, such vaccines induce killer T cells to attack tumor cells while leaving healthy cells unharmed. Schreiber’s group previously showed that more effective vaccines also activate helper T cells, another immune cell type, that recruit and expand additional killer T cells to destroy the tumors. But when they tried to add increased amounts of the helper T cell target to supercharge the vaccine they found they generated a different type of T cell that inhibited rather than promoted tumor rejection.

“We tested the hypothesis that by increasing helper T cell activation we would induce enhanced elimination of the sarcoma tumors in mice,” said first author Hussein Sultan, PhD, an instructor in pathology & immunology. So he injected groups of tumor bearing mice with vaccines that activated killer T cells equally while triggering a different degree of helper T cell activation.

Much to the researchers’ surprise in this latest study, the vaccine meant to hyperactivate helper T cells produced the opposite effect and inhibited tumor rejection.

“We thought that more helper T cell activation would optimize elimination of the sarcoma tumors in mice,” Sultan said. “Instead, we found that vaccines containing high doses of helper T cell targets induced inhibitory Tr1 cells that completely blocked tumor elimination. We know that Tr1 cells normally control an overactive immune system, but this is the first time they have been shown to dampen its fight against cancer.”

Tr1 cells normally put the brakes on the immune system to prevent it from attacking the body’s healthy cells. But their role in cancer has not been seriously explored. Looking through previously published data, the researchers found that tumors from patients who had responded poorly to immunotherapy had more Tr1 cells compared with tumors of patients who had responded well. The number of Tr1 cells also increased in mice as tumors grew bigger, rendering the mice insensitive to immunotherapy.

To bypass the inhibiting cells, the researchers treated the vaccinated mice with a drug that enhances killer T cells’ fighting power. The drug, developed by biotechnology startup Asher Biotherapeutics, carries modifications in the immune-boosting protein called interleukin 2 (IL-2) that specifically revs up killer T cells and reduces the toxicity of unmodified IL-2 treatments. The additional boost from the drug overcame Tr1 cells’ inhibition and rendered the immunotherapy more effective.

“We are committed to personalizing immunotherapy and broadening its effectiveness,” said Schreiber. “Decades of researching basic tumor immunology have expanded our understanding of how to trigger the immune system to achieve the most robust antitumor response. This new study adds to our understanding of how to improve immunotherapy to benefit more people.”

As co-founder of Asher Biotherapeutics — which provided the mouse version of the modified IL-2 drugs — Schreiber is indirectly involved in the company’s clinical trials testing the human version of the drug as a monotherapy in cancer patients. If successful, the drug has the potential to be tested in combination with cancer treatment vaccines.

To help protect drivers and machine operators from the dangers of drifting off, engineers at the University of California, Berkeley, have created prototype earbuds that can detect the signs of drowsiness in the brain.

The earbuds detect brain waves in the same way as an electroencephalogram (EEG), a test that doctors use to measure electrical activity in the brain. While most EEGs detect brain waves using a series of electrodes attached to the head, the earbuds do so using built-in electrodes that are designed to make contact with the ear canal.

The electrical signals detected by the ear buds are smaller than those picked up by a traditional EEG. However, in a new study, the researchers show that their Ear EEG platform is sensitive enough to detect alpha waves, a pattern of brain activity that increases when you close your eyes or start to fall asleep.

“I was inspired when I bought my first pair of Apple’s AirPods in 2017. I immediately thought, ‘What an amazing platform for neural recording,'” said study senior author Rikky Muller, an associate professor of electrical engineering and computer sciences at UC Berkeley. “We believe that this technology has many potential uses, and that classifying drowsiness is a good indicator that the technology can be used to classify sleep and even diagnose sleep disorders.”

Using an earbud as an EEG electrode poses a variety of practical challenges. In order to obtain an accurate EEG, electrodes need to make good contact with the skin. This is relatively easy to achieve in traditional EEGs, which use flat metal electrodes stuck to the scalp. However, it is much trickier to design an earbud that will fit snugly — and comfortably — in a wide variety of ear sizes and shapes.

When Muller’s team started working on the project, other groups developing Ear EEG platforms were either using wet electrode gels to ensure a good seal between the earbud and the ear canal, or creating custom-molded earpieces for each individual user. She and her team wanted to design a model that was dry and user generic, so that anyone could stick them in their ears and get reliable readings.

“My personal goal was to try to make a device that could be used every day by someone who would really benefit from it,” said Ryan Kaveh, a UC Berkeley postdoctoral scholar and co-first author of the study. “In order to do that, I knew that it would have to be reusable, fit a variety of people, and [be] easy to manufacture.”

Kaveh co-led the study with graduate student Carolyn Schwendeman and collaborated with Ana Arias’s lab at UC Berkeley to design the final earpiece in three sizes: small, medium and large. The earpiece incorporates multiple electrodes in a cantilevered design that applies gentle outward pressure to the ear canal and uses flexible electronics to ensure a comfortable fit. The signals are read out through a custom, low-power, wireless electronic interface.

In a 2020 paper, the researchers showed that these earpieces can detect a number of physiological signals, including eye blinks, alpha brain waves and the auditory steady-state response, which is the brain’s response to hearing a steady pitch. In the new study, they improved the earpiece design and incorporated machine learning to demonstrate how the earpieces could be used in a real-world application.

As part of the experiment, they asked nine volunteers to wear the earpieces while doing a series of boring tasks in a darkened room. Every so often, the volunteers were asked to rate their level of drowsiness, and their response times were measured.

“We found that even when the signal quality from the earpieces seemed worse, we could still classify the onset of drowsiness with the same level of accuracy as much more complicated, bulky systems,” Kaveh said. The earpieces also retain their accuracy when categorizing drowsiness in brand-new users, a characteristic of devices that could work ‘out of the box’.

Muller, who developed the Ear EEG with the support of the Bakar Fellowship and the Bakar Prize, is continuing to refine the design and explore other potential applications of the device, which can also record signals beyond EEG, such as heart beats, eye movements and jaw clenches.

“Wireless earbuds are something we already wear all the time,” Muller said. “That’s what makes Ear EEG such a compelling approach to wearables. It doesn’t require anything extra.”

This study was supported in part by the Ford University Research Program and a Bakar Spark Award.

A recent study from the University of Illinois Urbana-Champaign and the University of Pretoria in South Africa demonstrates how African conservation managers could create and optimize elephant movement corridors across a seven-country region. The study offers a map showing landscape connections that would support elephants’ habitat needs and allow for more gene flow among populations.

“Other research groups have integrated genetic and spatial data before, but usually it’s done on a more local scale. Ours was the first to combine both types of data for southern African elephants across such a large geographic area,” said lead author Alida de Flamingh, who completed the study as part of her doctoral program in the Department of Animal Sciences, part of the College of Agricultural, Consumer and Environmental Sciences (ACES) at Illinois. She is now a postdoctoral researcher at the Carl R. Woese Institute for Genomic Biology.

Scale is meaningful because African elephants have very large home ranges — roaming up to 11,000 square kilometers, or more than 2.7 million acres — and they often travel long distances out of their way to avoid unsuitable habitat. Capturing that scale in a single analysis was no easy feat.

“This was a massive effort. We went out with our partners in the Conservation Ecology Research Unit at the University of Pretoria to collect non-invasive DNA samples from elephant dung across the whole range,” de Flamingh said. “CERU also contributed data from GPS trackers on 80 collared elephants across nearly 54,000 locations.”

GPS collar data shows how elephants move across the landscape but can’t indicate whether that movement leads to gene flow. Conversely, DNA data documents gene flow, but can’t show how elephants moved to make that happen. Integrating the two data sets required a landscape genetics approach.

“Landscape genetics adapts some ideas from electrical circuit theory to discuss how animals might move and achieve gene flow. Our approach looks at resistances or costs elephants encounter as they move along multiple pathways through the region, accounting for the possibility of losing or gaining individual paths,” said co-author Nathan Alexander, a postdoctoral researcher at the Illinois Natural History Survey. Alexander worked on the project during his doctoral program in the Department of Natural Resources and Environmental Sciences in ACES.

Costs in this case included steep slopes, barren areas with little to no vegetation, densely populated human settlements, and areas far from water. The researchers combined these environmental challenges with DNA data to explain how elephants might navigate their habitat, identifying key routes to maintain gene flow across protected areas.

“We did not find a simple linear relationship where more suitable habitats are less costly. Instead, we found a pronounced nonlinear pattern where the least suitable habitats have the biggest impact on elephant movement or distribution across the landscape,” de Flamingh said. “Intermediate habitats aren’t necessarily dictating their movements as much as these really, really unsuitable habitats. That’s positive, if you think about it. They’re tolerant of intermediate habitats and can still move through them.”

What qualifies as a “really, really unsuitable” habitat? The researchers identified areas like the vegetation-free Makgadikgadi salt pans in Botswana, as well as densely populated human settlements. Providing connections for elephants that avoid these areas will also reduce human-elephant conflict, a distinct threat to elephants.

De Flamingh said the insights gained from this study can help governmental authorities and NGOs in southern Africa to develop robust conservation initiatives on the ground.

“Southern Africa has the largest number of elephants in all of Africa. So any conservation efforts there, especially those that avoid human-elephant conflict, would protect pretty large populations of elephants,” said senior author Al Roca, an animal sciences professor in ACES. “Our partners at CERU, as well as our funders — the International Fund for Animal Welfare and the African Elephant Conservation Fund of the U.S. Fish and Wildlife Service — are really critical in those efforts.”

The study, “Integrating habitat suitability modeling with gene flow improves delineation of landscape connections among African savanna elephants,” is published in Biodiversity and Conservation. The paper is dedicated to the memory of co-author Rudi van Aarde, who was instrumental in launching the study as head of CERU, and who passed away while the research was ongoing.

Roca is also affiliated with the Carl R. Woese Institute for Genomic Biology, the Illinois Natural History Survey, and the School of Information Sciences at Illinois.

“Over that embryonic period [up to eight weeks from conception], triploidy had rarely been reported in mammals outside of women,” said Mandi de Mestre, professor of equine medicine at Cornell University. “The study tells us that over the first six weeks of gestation, this will likely be the primary cause of pregnancy loss following natural conception.”

de Mestre is the corresponding author of “Naturally Occurring Horse Model of Miscarriage Reveals Temporal Relationship Between Chromosomal Aberration Type and Point of Lethality,” published in the Proceedings of the National Academy of Sciences.

Human miscarriages occur in 10-20% of pregnancies and are commonly associated with chromosomal errors, but there have been no suitable animal models that truly duplicate the features of the condition. The new research findings will help veterinarians better understand the causes of pregnancy loss in horses and identifies horses as an excellent model for studying human miscarriage.

“We were able to study the impact of chromosome errors across the entire pregnancy in the horse,” de Mestre said. “We found that triploidy is only associated with losses in early pregnancy.”

In the study, de Mestre’s laboratory at Cornell, and earlier at The Royal Veterinary College, London, received 256 fetus and placenta samples from veterinarians who treated horses with failed pregnancies over a period of 10 years. Using the samples, the researchers were able to investigate the prevalence of different types of chromosomal copy number errors associated with pregnancy loss. They found that chromosomal errors occurred in 57.9% of pregnancy losses up to day 55 of gestation, in 57.2% of losses between days 56 and 110 and in only 1.4% of losses between days 111 and the end of pregnancy. Aneuploidy (loss or gain of a single whole chromosome) was mainly associated with miscarriages in the first 10 weeks of pregnancy, while deletions or duplications of only part of a chromosome were found in miscarriages after 110 days. These findings turned out to be remarkably similar to those observed in a number of large studies in women, according to the paper.

Horses are a good model for studying human pregnancies because they have a similar gestation period — 11 months compared to nine months in women — and the embryo develops at a similar rate in the early stages. In addition, horse chromosomes have a very similar genetic content to human chromosomes, which makes them particularly relevant for the study of chromosome errors.

Reasons for miscarriage in women in very early pregnancy have been difficult to determine because most fetuses during this period are lost at home, leaving scientists without material — and data — to study. The study’s findings provide insight into the frequency of chromosome errors over the equivalent period of the first six weeks of human gestation.

Because of the value of horses and the emotional attachment their owners have to them, horses receive a high level of care, with routine tracking of pregnancies, which then provide extensive data for research.

Other animal models, such as mice, are not comparable to human pregnancies. Mice have a gestation period of about three weeks, and natural pregnancy losses in mice are low.

In terms of equine health, the study provides new details about common chromosomal abnormalities that will likely change the clinical management of pregnancies. For example, if a clinician determines that a horse has a major chromosomal error, they may no longer choose to extend that pregnancy by administering hormones, a common practice in pregnant mares. The study will also point researchers toward the development of new diagnostic tests for chromosome abnormalities in horse fetuses and investigating molecular mechanisms that lead to these abnormalities.

“This research has provided a foundation for understanding the genetic causes of pregnancy loss in horses, often referred to as pregnancy loss of unknown cause,” said Shebl Salem, a postdoctoral researcher in de Mestre’s Equine Pregnancy Lab and a co-first author of the study.

Other co-first authors include Jessica Lawson of the Royal Veterinary College in London, United Kingdom; and Donald Miller, de Mestre lab manager.

The study was partly funded by the Horserace Betting Levy Board and Thoroughbred Breeders Association.