(Press-News.org) Immunologists at St. Jude Children's Research Hospital have discovered that tumors use a unique mechanism to switch on regulatory T cells to protect themselves from attack by the immune system. Surprisingly, the mechanism does not affect regulatory T cell function outside the tumor and may therefore limit the immune-associated toxicities of targeting regulatory T cells.
The finding offers the promise of drug treatment to selectively shut down regulatory T cells in a tumor, rendering the tumor vulnerable to cancer immunotherapies that activate the immune system to kill the tumor. The researchers showed that blocking tumor-associated regulatory T cell activity eliminated tumors cells in mice and sensitized the cells to cancer immunotherapy called anti-PD-1 therapy.
The research appeared today in the journal Nature.
A tumor-controlled metabolic pathway to ward off the immune system
Regulatory T cells keep the immune system in check, preventing it from attacking the body's own tissues in autoimmune diseases such as lupus and rheumatoid arthritis.
"There has certainly been a great deal of interest in targeting regulatory T cells for cancer therapy, because they are central to keeping the immune system in check in tumors," said corresponding author Hongbo Chi, Ph.D., of the St. Jude Department of Immunology. "But the risk of such targeting is possibly inducing autoimmune disease because these T cells are crucial to balancing the body's immune response.
"Our finding is exciting because we have identified a metabolic pathway that tumors use to independently reprogram regulatory T cells," he said. "Thus, we believe there is the potential for inhibiting regulatory T-cell activation in tumors to unleash effective antitumor immune responses without triggering autoimmune toxicity."
Tracking gene regulation to a surprise
Researchers discovered the pathway by challenging mice with melanoma cells and then analyzing which genes were switched on in regulatory T cells. Investigators compared tumor-infiltrating regulatory T cells with regulatory T cells in other tissues to compare gene activation.
The experiment revealed a master genetic switch that was activated only in regulatory T cells in the tumor microenvironment. The switch was a transcription factor family called SREBP.
"We were surprised to find this context-dependent pathway functioning selectively in the tumor microenvironment," Chi said. Seon Ah Lim, Ph.D., a first author of the study, added, "It is incredible we can target metabolic pathways in regulatory T cells for cancer immunotherapy while maintaining immune homeostasis."
The researchers determined that the tumor-specific regulatory T cell pathway was switched on in a range of cancers--melanoma, breast cancer and head and neck cancer. The tumor-specific pathway was not switched on in animal models of inflammation or autoimmune disease.
Genetically blocking the SREBP pathway selectively in regulatory T cells led to rapid clearance of tumor cells in mice with melanoma and colon adenocarcinoma. Targeting the pathway also reduced tumor growth in mice with established tumors. Blocking the pathway had no effect on the proliferation of regulatory T cells or their overall function in the body.
Blocking a pathway unleashes the anti-cancer immune response
Blocking the SREBP pathway also unleashed a potent antitumor response in mice with melanoma treated with immunotherapy called anti-PD-1. Anti-PD-1 treatment alone was otherwise ineffective in the mice. This form of immunotherapy inhibits the biochemical switch known as programmed cell death protein 1, or PD-1. PD-1 is a checkpoint switch that protects tumors by suppressing the immune response to them.
"Anti-PD-1 therapy currently works in only about 20% of cancer patients, although when it works, the response is durable in those cases," Chi said. "Many pediatric cancers are not responsive to anti-PD-1. Our experiments showed that blocking this lipid pathway had quite a remarkable effect in sensitizing mice to the therapy.
"While we still have a long research path ahead of us, these findings suggest that if we can develop drugs to control this context-specific regulatory T cell pathway in cancer patients, we can make them even more responsive to immunological checkpoint therapies," he said.
INFORMATION:
Jun Wei of St. Jude is the other first author. The other authors are Thanh-Long Nguyen, Hao Shi, Wei Su, Gustavo Palacios, Yogesh Dhungana, Nicole Chapman, Lingyun Long, Jordy Saravia and Peter Vogel, all of St. Jude.
The research was supported by in part by the National Institutes of Health (CA221290, CA250533, AI105887, AI131703, AI140761, AI150241 and AI150514) and ALSAC, the St. Jude fundraising and awareness organization.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer and other life-threatening diseases. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 50 years ago. St. Jude freely shares the breakthroughs it makes, and every child saved at St. Jude means doctors and scientists worldwide can use that knowledge to save thousands more children. Families never receive a bill from St. Jude for treatment, travel, housing and food -- because all a family should worry about is helping their child live. To learn more, visit stjude.org or follow St. Jude on social media at @stjuderesearch.
BROOKLYN, New York, Wednesday, February 24, 2021 -The Governance Lab (The GovLab) at the NYU Tandon School of Engineering released a report, "The Power of Virtual Communities," which examines the role online groups play in creating opportunities for people to build new kinds of meaningful communities they often could not form in real space.
This first-of-its-kind research was built on interviews with 50 Facebook community leaders in 17 countries, 26 global experts from academia and industry, unique access to Facebook's underlying research and an original global survey conducted by YouGov of 15,000 people in 15 countries who are currently members of online and ...
Aged cheeses pack a punch of nutty, sharp flavor. Before they're fully mature, aged cheeses are either waxed or placed in brine for weeks to create a natural rind. However, the high salt content in brined cheeses deters some consumers. Now, researchers reporting in ACS Food Science & Technology present a shortened brining time for Parmigiano Reggiano that results in a less salty product, while still potentially maintaining the cheese's distinctive texture and flavor compounds.
Parmigiano Reggiano is a lactose-free, crumbly and hard cheese. Manufactured ...
Scientists have made a pivotal breakthrough in the quest to understand how single-cell green algae are able to keep track of the light as they swim.
A team of researchers from the University of Exeter's flagship Living Systems Institute has discovered how the model alga Chlamydomonas is seemingly able to scan the environment by constantly spinning around its own body axis in a corkscrewing movement. This helps it respond to light, which it needs for photosynthesis.
The tiny alga, which is found abundantly in fresh-water ponds across the world, swims by beating its two flagella, hair-like structures that adopt a whip-like movement to move the cell. These flagella beat in much the same way as the cilia in the human respiratory ...
NEW YORK (February 24, 2021) -- Nearly half of women with uncomplicated urinary tract infections received the wrong antibiotics and almost three-quarters received prescriptions for longer than necessary, with inappropriately long treatment durations more common in rural areas, according to a study of private insurance claims data published today in Infection Control & Hospital Epidemiology, the journal of the Society for Healthcare Epidemiology of America.
"Inappropriate antibiotic prescriptions for uncomplicated urinary tract infections are prevalent and come with serious patient- and society-level consequences," said Anne Mobley Butler, PhD, lead author of the study and assistant professor ...
In the first few months of their lives, babies cry, babble, gurgle and make a variety of other peculiar sounds. It can be difficult to imagine that they are actually laying the foundations for later speech with these utterances. However, there is a determining element that proves that even their cries can be assigned to a particular language: the speech melody - or, more accurately: prosody.
"Every language is characterised by specific musical elements, which we call prosody," says Kathleen Wermke. Prosody, in simple terms, is the combination of intonation (melody) and rhythm. Earlier studies have shown that even newborns are able to distinguish different languages, like German ...
Everyone knows 2 + 2 = 4, but what about mosquitoes plus malaria? Lauren Childs, an assistant professor in the Department of Mathematics at Virginia Tech, says there's an equation for that too.
Childs recently co-authored a report with a team from Harvard University on the role of natural mosquito behavior on transmission of a disease that threatens half the world's population.
The study, "Multiple blood feeding in mosquitoes shortens the Plasmodium falciparum incubation period and increases malaria transmission potential," was published in the December 2020 issue of PLOS Pathogens.
"Worldwide there are about 400,000 deaths and 200 million cases each year from malaria," said Childs, a faculty member with the Virginia Tech College ...
Prisons with more green space have lower levels of violence and self-harm, according to new research at the University of Birmingham and Utrecht University.
The study is the first to attempt large-scale mapping of green space within prison environments and link it to well-being in a robust, statistically significant way. The results are published in Annals of the American Association of Geographers.
The researchers used GIS mapping to identify the percentages of green space (such as trees, lawns and shrubbery) within prisons in England and Wales. They ...
A new report shows that British citizens who are missing abroad were more than twice as likely to be found by UK police as police in the country of disappearance.
Research by the Centre for the Study of Missing Persons (CSMP) at the University of Portsmouth also shows they were likely to be missing for much longer than if they'd disappeared in the UK.
The study found that British people who vanish abroad tend to be missing for extended periods, on average 134 days. This compares with 88 percent of people who go missing in the UK being found within the first 48 hours.
Dr Karen Shalev-Greene, Director of the ...
Extreme weather driven by climate change is making power outages more commonplace even as the need for electricity-dependent home health equipment grows. In this context, battery storage can help protect medically vulnerable households, according to researchers at Columbia University Mailman School of Public Health. The article is published in the journal Futures.
For the millions reliant on electricity for home medical equipment, even short-term power outages can lead to a potentially life-threatening situation. Society's most vulnerable populations--elders, ...
Heads or tails? If we toss two coins into the air, the result of one coin toss has nothing to do with the result of the other. Coins are independent objects. In the world of quantum physics, things are different: quantum particles can be entangled, in which case they can no longer be regarded as independent individual objects, they can only be described as one joint system.
For years, it has been possible to produce entangled photons - pairs of light particles that move in completely different directions but still belong together. Spectacular results have been achieved, for example in the field of quantum teleportation or quantum cryptography. Now, a new method has been ...
