Newswise — A team of researchers from the University of Chicago, in collaboration with researchers from the University of Pittsburgh, has identified a novel oncometabolite that accumulates in tumors and impairs immune cells’ ability to fight cancer.
The , published in Nature Cell Biology, highlights how the metabolic environment of tumors influences the function of T cells, which are critical immune cells responsible for eliminating cancer. The finding opens new possibilities for improving cancer immunotherapy by targeting tumor metabolism.
Metabolic barriers in the tumor microenvironment
The tumor microenvironment — the complex environment that surrounds cancer cells — is often deprived of nutrients and oxygen, particularly in hard-to-treat cancers like pancreatic cancer. To survive these harsh conditions, cancer cells adapt by reprogramming their metabolism.
T cells are essential for mounting an effective immune response against tumors. However, once they enter the tumor environment, they are exposed to various stressors that alter their development and function, pushing them toward a dysfunctional and exhausted state.
T cell activity is tightly regulated by their metabolic processes. In tumors, abnormal blood vessels and the disrupted metabolism of cancer cells lead to nutrient shortages and a buildup of metabolic waste. These imbalances in the tumor microenvironment can interfere with T cell metabolism, impairing their ability to function effectively.
“We are interested in exploring what nutrients are present and which ones are missing in the tumor microenvironment,” said , Assistant Professor in the Ben May Department of Cancer Research at UChicago and co-senior author of the paper.
Co-senior author Greg Delgoffe, PhD, Professor of Immunology at the University of Pittsburgh and Director of the Tumor Microenvironment Center at UPMC Hillman Cancer Center, elaborated: “Cancer cells have a voracious appetite, consuming all of the food in the tissue around them and leaving very little for infiltrating immune cells to eat. However, no one had systematically measured exactly how cancer cells change their local nutrient conditions and how those metabolites affect immunity.”
To better understand the metabolic landscape, Muir’s team developed a tool capable of measuring the concentration of hundreds of nutrients typically found in tumors. The team analyzed 118 major nutrients to determine which metabolic deficiencies might be driving T cell dysfunction in certain tumor microenvironments.
A surprising discovery: Not nutrient shortage, but metabolite build-up
In their previous work, Muir’s team found that T cells multiply and function differently when grown in nutrient solution mimicking the levels of nutrients found in tumors. Their latest study focused on understanding how T cells function in the presence of the unique metabolic products/conditions found in tumors.
The study results were surprising: an excess of a certain metabolite, rather than a shortage of nutrients, appeared to be the cause of T cell dysfunction. Their analysis of T cells grown in tumor-like nutrients revealed an unusually high accumulation of phosphoethanolamine, a metabolite that suppresses T cell interaction with cancer cells.
“We are not quite sure how phosphoethanolamine accumulates in such high amounts, but every tumor we’ve examined — whether human or mouse — shows a huge build-up of it,” Muir said. “We now know that this metabolite interacts with T cells and suppresses their ability to target and kill cancer cells. It may represent a common strategy tumors use to evade immune detection.”
Implications for cancer immunotherapy
T cells play a central role in the body’s natural defense against cancer. Treatments that enhance T cell activity, such as immunotherapies, have revolutionized cancer treatment in recent years. However, these therapies don’t work for many patients, often due to T cell dysfunction in tumors.
“Our approach is not just to observe that T cells stop working, but to figure out what is happening behind the scenes so we can hopefully prevent it in the future,” said Muir, who is also the assistant leader of the Molecular Mechanisms of Cancer research program in the UChicago Medicine Comprehensive Cancer Center.
The researchers suggest measuring tumor metabolites like phosphoethanolamine could serve as a diagnostic tool and help identify new drug targets aimed at restoring immune cell function in tumors.
“By better understanding the metabolic landscape within the tumor microenvironment, we can hopefully design more effective treatments that overcome these hidden barriers,” Muir said.
Blocking the metabolite’s effect
The research team is now working to uncover why phosphoethanolamine accumulates in tumors and develop strategies to block its effects on immune cells.
Delgoffe added, “The future of this project is to determine if phosphoethanolamine may be a biomarker of tumor burden or even tumor-induced immune suppression, which could help us determine who might respond to immune-based therapies for cancer.”
He noted that “the team is also interested in designing next-generation therapeutic strategies to reduce the levels of phosphoethanolamine in tumors with the goal of limiting immunosuppression and boosting immunotherapy.”
“We are really excited about this, because it’s giving us a potential way to intervene and improve T cell function in fighting tumors,” Muir said.
The study, “” was supported by the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, the Brinson Foundation, the Cancer Research Foundation, the Cancer Research Institute, the Mark Foundation, and the Pittsburgh Foundation.
Additional authors include Yupeng Wang from Tsinghua Medical School, Beijing, China; Benjamin Cameron, Emerson Schoedel, William Gunn, Drew Wilfahrt, Bingxian Xie, Ronal Peralta, Dayana Rivadeneira from the University of Pittsburgh, Pittsburgh; Patrick Jonker, Konstantinos Lontos, Chufan Cai, Roya Amini Tabrizi, and Hardik Shah from the University of Chicago, Chicago.
UChicago Medicine is designated as a Comprehensive Cancer Center by the National Cancer Institute, the most prestigious recognition possible for a cancer institution. We have more than 200 physicians and scientists dedicated to defeating cancer.
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