Obesity impairs immune cell function, accelerates tumor growth

Cancer definition

Obesity has been linked to increased risk for over a dozen different types of cancer, as well as worse prognosis and survival. Over the years, scientists have identified obesity-related processes that drive tumor growth, such as metabolic changes and chronic inflammation, but a detailed understanding of the interplay between obesity and cancer has remained elusive.

Now, in a study in mice, Harvard Medical School researchers have uncovered a new piece of this puzzle, with surprising implications for cancer immunotherapy: Obesity allows cancer cells to outcompete tumor-killing immune cells in a battle for fuel.

Reporting in Cell on Dec. 9, the research team shows that a high-fat diet reduces the numbers and antitumor activity of CD8+ T cells, a critical type of immune cell, inside tumors. This occurs because cancer cells reprogram their metabolism in response to increased fat availability to better gobble up energy-rich fat molecules, depriving T cells of fuel and accelerating tumor growth.

"Putting the same tumor in obese and nonobese settings reveals that cancer cells rewire their metabolism in response to a high fat diet," said Marcia Haigis, professor of cell biology in the Blavatnik Institute at HMS and co-senior author of the study. "This finding suggests that a therapy that would potentially work in one setting might not be as effective in another, which needs to be better understood given the obesity epidemic in our society."

The team found that blocking this fat-related metabolic reprogramming significantly reduced tumor volume in mice on high-fat diets. Because CD8+ T cells are the main weapon used by immunotherapies that activate the immune system against cancer, the study results suggest new strategies for improving such therapies.

"Cancer immunotherapies are making an enormous impact on patients' lives, but they do not benefit everyone," said co-senior author Arlene Sharpe, the HMS George Fabyan Professor of Comparative Pathology and chair of the Department of Immunology in the Blavatnik Institute.

"We now know there is a metabolic tug-of-war between T cells and tumor cells that changes with obesity," Sharpe said. "Our study provides a roadmap to explore this interplay, which can help us to start thinking about cancer immunotherapies and combination therapies in new ways."

Haigis, Sharpe and colleagues investigated the effects of obesity on mouse models of different types of cancer, including colorectal, breast, melanoma and lung. Led by study co-first authors Alison Ringel and Jefte Drijvers, the team gave mice normal or high-fat diets, the latter leading to increased body weight and other obesity-related changes. They then looked at different cell types and molecules inside and around tumors, together called the tumor microenvironment.

Researchers develop rapid genomics strategy to trace coronavirus

 

Coronavirus illustration

Thanks to cutting-edge 'Nanopore' genome sequencing technology, researchers at the Garvan Institute of Medical Research and the Kirby Institute at UNSW Sydney have developed the most rapid coronavirus genome sequencing strategy in Australia to date. The technological advance has the potential to provide critical, timely clues on how cases of SARS-CoV-2 infection are linked.

The researchers today published an analytical validation and best practice guidelines for Nanopore sequencing of SARS-CoV-2 in Nature Communications, which they hope will enable a greater uptake of the fast sequencing technology for health initiatives in Australia and overseas.

"Every time the SARS-CoV-2 virus passes from person to person, it may make copying errors that change a couple of its 30,000 genetic letters. By identifying this genetic variation, we can establish how different cases of coronavirus are linked -- to know where a case was potentially picked up from and who they may have given it to," says co-first author A/Prof Rowena Bull, from UNSW's Kirby Institute.

A/Prof Bull says genomic testing is crucial for tracking virus transmission in cases where the source remains unclear from investigating known epidemiological contacts alone.

"By reconstructing the virus's evolutionary history, or 'family tree', we can understand the behaviours that help spread COVID-19 and identify so-called 'super-spreaders'," she says.

"When a new 'mystery' coronavirus case is identified, every minute counts. At Garvan, we have repurposed our genomic sequencing capabilities to enable a rapid analysis of a coronavirus genome in just a few hours," says senior author Dr Ira Deveson, Head of the Genomic Technologies Group at Garvan's Kinghorn Centre for Clinical Genomics.

"We've been thrilled to collaborate with the Garvan and Kirby Institutes to develop unparalleled speeds of coronavirus genome testing. Rapid methods such as this provide a way forward, as a potential future option for contact tracing through real time genomic transmission studies," says Prof Bill Rawlinson AM, from UNSW Sydney and NSW Health Pathology Randwick.

"This technical advance is a testament to what's possible when public pathology collaborates with Research Institutes for a common goal," says Prof Sebastiaan van Hal, from NSW Health Pathology -- Royal Prince Alfred Hospital.

Pioneering rapid genomics

Pinpointing SARS-CoV-2 transmission quickly is crucial. NSW Health Pathology has collaborated with the Garvan Institute and Kirby Institute to develop faster SARS-CoV-2 genome sequencing capabilities, potentially enhancing the ability of contact tracers to take rapid action to quarantine and monitor potential contacts. Garvan researchers have fine-tuned the protocols for cutting-edge Oxford Nanopore Technologies to sequence SARS-CoV-2 in less than four hours. Garvan's Kinghorn Centre for Clinical Genomics is the first facility in Australia to establish and apply this Nanopore technology for genomic surveillance of SARS-CoV-2.

Highly accurate emerging technologies

The current gold-standard method reads short genetic sequences of just 100-150 genetic letters at a time, whereas Nanopore technologies have no upper limit to the length of DNA fragments that can be sequenced and are able to more rapidly determine the complete sequence of a viral genome.

"However, as with many emerging technologies, there have been concerns about the accuracy of Nanopore sequencing. We addressed these concerns in our paper where we report the outcomes of a rigorous analytical evaluation of our protocols for sequencing the coronavirus genome," says Dr Deveson.

The researchers' analysis revealed the Nanopore sequencing method to be highly accurate (variants were detected with >99% sensitivity and >99% precision in 157 SARS-CoV-2-positive patient specimens) and provides best practice guidelines, which the researchers hope will promote the uptake of the technology by other teams globally.

The researchers say Nanopore sequencing even has the potential to enhance SARS-CoV-2 surveillance by enabling point-of-care sequencing and improved turnaround times for critical cases.

"Nanopore devices are cheaper, faster, portable and don't require the lab infrastructure needed by current standard pathogen genomics tools," says Dr Deveson. "We hope our validation of this protocol will help other public health teams around the world adopt this technology."

Plastics pose threat to human health, report shows

Bulldozer at landfill

Plastics contain and leach hazardous chemicals, including endocrine-disrupting chemicals (EDCs) that threaten human health. An authoritative new report, "Plastics, EDCs, and Health," from the Endocrine Society and the IPEN (International Pollutants Elimination Network), presents a summary of international research on the health impacts of EDCs and describes the alarming health effects of widespread contamination from EDCs in plastics.

EDCs are chemicals that disturb the body's hormone systems and can cause cancer, diabetes, reproductive disorders, and neurological impairments of developing fetuses and children. The report describes a wealth of evidence supporting direct cause-and-effect links between the toxic chemical additives in plastics and specific health impacts to the endocrine system.

Conservative estimates point to more than a thousand manufactured chemicals in use today that are EDCs. Known EDCs that leach from plastics and threaten health include bisphenol A and related chemicals, flame retardants, phthalates, per- and polyfluoroalkyl substances (PFAS), dioxins, UV-stabilizers, and toxic metals such as lead and cadmium. Plastic containing EDCs is used extensively in packaging, construction, flooring, food production and packaging, cookware, health care, children's toys, leisure goods, furniture, home electronics, textiles, automobiles and cosmetics.

Key findings in the report include:

• One hundred and forty four chemicals or chemical groups known to be hazardous to human health are actively used in plastics for functions varying from antimicrobial activity to colorants, flame retardants, solvents, UV-stabilizers, and plasticizers.
• Exposure can occur during the entire life span of plastic products, from the manufacturing process to consumer contact, recycling, to waste management and disposal.
• EDC exposure is a universal problem. Testing of human samples consistently shows nearly all people have EDCs in their bodies.
• Microplastics contain chemical additives, which can leach out of the microplastic and expose the population. They can also bind and accumulate toxic chemicals from the surrounding environment, such as seawater and sediment, functioning as carriers for toxic compounds.
• Bioplastics/biodegradable plastics, promoted as more ecological than plastics, contain similar chemical additives as conventional plastics and also have endocrine-disrupting effects.

"Many of the plastics we use every day at home and work are exposing us to a harmful cocktail of endocrine-disrupting chemicals," said the report's lead author, Jodi Flaws, Ph.D., of the University of Illinois at Urbana-Champaign in Urbana, Ill. "Definitive action is needed on a global level to protect human health and our environment from these threats."

The Swiss Ambassador for the Environment, Franz Xavier Perrez, commented, "'Plastics, EDCs, and Health,' synthesizes the science on EDCs and plastics. It is our collective responsibility to enact public policies to address the clear evidence that EDC in plastics are hazards threatening public health and our future."

In May, the Swiss Government submitted a proposal to the Stockholm Convention to list the first ultra-violet (UV) stabilizer, plastic additive UV-328, for listing under the Stockholm Convention. UV stabilizers are a common additive to plastics and are a subset of EDCs described in this report. The Stockholm Convention is the definitive global instrument for assessing, identifying, and controlling the most hazardous chemical substances on the planet.

The need for effective public policy to protect public health from EDCs in plastics is all the more urgent given the industry's dramatic growth projections. Pamela Miller, IPEN Co-Chair, commented, "This report clarifies that the current acceleration of plastic production, projected to increase by 30-36% in the next six years, will greatly exacerbate EDC exposures and rising global rates of endocrine diseases. Global policies to reduce and eliminate EDCs from plastic and reduce exposures from plastic recycling, plastic waste, and incineration are imperative. EDCs in plastics are an international health issue that is felt acutely in the global south where toxic plastic waste shipments from wealthier countries inundate communities."

"Endocrine-disrupting chemical exposure is not only a global problem today, but it poses a serious threat to future generations," said co-author Pauliina Damdimopoulou, Ph.D., of the Karolinska Institutet in Stockholm, Sweden. "When a pregnant woman is exposed, EDCs can affect the health of her child and eventual grandchildren. Animal studies show EDCs can cause DNA modifications that have repercussions across multiple generations."

 

COVID-19 virus enters the brain, research strongly suggests

Coronavirus illustration 

More and more evidence is coming out that people with COVID-19 are suffering from cognitive effects, such as brain fog and fatigue.

And researchers are discovering why. The SARS-CoV-2 virus, like many viruses before it, is bad news for the brain. In a study published Dec.16 in Nature Neuroscience, researchers found that the spike protein, often depicted as the red arms of the virus, can cross the blood-brain barrier in mice.

This strongly suggests that SARS-CoV-2, the cause of COVID-19, can enter the brain.

The spike protein, often called the S1 protein, dictates which cells the virus can enter. Usually, the virus does the same thing as its binding protein, said corresponding author William A. Banks, a professor of medicine at the University of Washington School of Medicine and a Puget Sound Veterans Affairs Healthcare System physician and researcher. Banks said binding proteins like S1 usually by themselves cause damage as they detach from the virus and cause inflammation.

"The S1 protein likely causes the brain to release cytokines and inflammatory products," he said.

In science circles, the intense inflammation caused by the COVID-19 infection is called a cytokine storm. The immune system, upon seeing the virus and its proteins, overreacts in its attempt to kill the invading virus. The infected person is left with brain fog, fatigue and other cognitive issues.

Banks and his team saw this reaction with the HIV virus and wanted to see if the same was happening with SARS CoV-2.

Banks said the S1 protein in SARS-CoV2 and the gp 120 protein in HIV-1 function similarly. They are glycoproteins -- proteins that have a lot of sugars on them, hallmarks of proteins that bind to other receptors. Both these proteins function as the arms and hand for their viruses by grabbing onto other receptors. Both cross the blood-brain barrier and S1, like gp120, is likely toxic to brain tissues.

"It was like déjà vu," said Banks, who has done extensive work on HIV-1, gp120, and the blood-brain barrier.

The Banks' lab studies the blood-brain barrier in Alzheimer's, obesity, diabetes, and HIV. But they put their work on hold and all 15 people in the lab started their experiments on the S1 protein in April. They enlisted long-time collaborator Jacob Raber, a professor in the departments of Behavioral Neuroscience, Neurology, and Radiation Medicine, and his teams at Oregon Health & Science University.

The study could explain many of the complications from COVID-19.

"We know that when you have the COVID infection you have trouble breathing and that's because there's infection in your lung, but an additional explanation is that the virus enters the respiratory centers of the brain and causes problems there as well," said Banks.

Raber said in their experiments transport of S1 was faster in the olfactory bulb and kidney of males than females. This observation might relate to the increased susceptibility of men to more severe COVID-19 outcomes.

As for people taking the virus lightly, Banks has a message:

"You do not want to mess with this virus," he said. "Many of the effects that the COVID virus has could be accentuated or perpetuated or even caused by virus getting in the brain and those effects could last for a very long time."

This study was partially supported by a National Institute on Aging-funded COVID-19 supplement to a shared RF1 grant of Banks and Raber.