Tumor by-products block immune cells in the fight against cancer, offering a new treatment target

A team of researchers from the University of Chicago, in collaboration with researchers from the University of Pittsburgh, has identified a new oncotabolite that accumulates in tumors and alters the ability of immune cells to fight cancer.

The study, published in Cellular biology of natureemphasizes how the metabolic environment of tumors influences the function of T cells, which are critical immune cells responsible for the elimination of cancer. Discovery opens up new possibilities to improve immunotherapy against cancer by targeting tumor metabolism.

Metabolic barriers in tumor microenvironment

Tumor microenvironnement – the complex environment surrounding cancer cells – is often deprived of nutrients and oxygen, especially in cancers that are difficult to treat such as pancreatic cancer. To survive these difficult conditions, cancer cells adapt by reprogramming their metabolism.

T cells are essential for mounting an effective immune response against tumors. However, once they have entered the tumor environment, they are exposed to various stressors that modify their development and function, pushing them to a dysfunctional and exhausted state.

The activity of T lymphocytes is closely regulated by their metabolic processes. In tumors, abnormal blood vessels and metabolism disturbed of cancer cells cause nutrient shortages and an accumulation of metabolic waste. These imbalances in tumor microenvironment can interfere with the metabolism of T lymphocytes, altering their ability to operate effectively.

“We want to explore which nutrients are present and which are missing in tumor microenvironment,” said Alexander Muir, Ph.D., assistant professor at the Ben Mayicago Research Department in Uchicago and Co-Sensior Author of the Journal.

The author Co-Senor Greg Delgoff, Ph.D., professor of immunology at the University of Pittsburgh and director of the Tumor Microenvironment Center of the UPMC Hillman Cancer Center, has developed: “cancer cells have a voracious appetite, consuming all the foods in the tissues that have been systematically measured for cancer cells, Immunes infiltrating have been eating.

To better understand the metabolic landscape, the Muir team has developed a tool capable of measuring the concentration of hundreds of nutrients that are generally found in tumors. The team analyzed 118 major nutrients to determine which metabolic deficiencies could stimulate the dysfunction of T lymphocytes in certain tumor micro-environment.

A surprising discovery: not a shortage of nutrients, but the accumulation of metabolite

In their previous work, the Muir team found that T cells are multiplying and operate differently when they are cultivated in a nutrient solution imitating the nutrient levels found in tumors. Their latest study focused on understanding the functioning of T cells in the presence of unique metabolic products / conditions found in tumors.

The results of the study were surprising: an excess of a certain metabolite, rather than a shortage of nutrients, seemed to be the cause of a dysfunction of T cells. Their analysis of cultivated T cells in tumor -type nutrients has revealed an unusually high accumulation of phosphoethanolamine, a metabolite that suppresses the interaction of T cells cancerous.

“We are not sure how phosphoethanolamine accumulates in such high quantities, but each tumor that we have examined – whether human or mouse – in fact a huge accumulation,” said Muir. “We now know that this metabolite interacts with T cells and removes their ability to target and kill cancer cells. It can represent a common strategy used by tumors to escape immune detection.”

Implications for cancer immunotherapy

T cells play a central role in the natural defense of the body against cancer. Treatments that improve the activity of T lymphocytes, such as immunotherapy, have revolutionized cancer treatment in recent years. However, these therapies do not work for many patients, often due to the dysfunction of T lymphocytes in tumors.

“Our approach is not only to observe that T cells stop working, but to understand what is happening behind the scenes so that we can hope to prevent it in the future,” said Muir, who is also the deputy chief of the molecular mechanisms of the research program on cancer in the Uchicago Medicine understanding Cancer Center.

Researchers suggest that the measurement of tumor metabolites such as phosphoethanolamine could serve as a diagnostic tool and help identify new drug targets aimed at restoring the function of immune cells in tumors.

“Better understanding the metabolic landscape within the tumor microenvironment, we can, hope, conceive more effective treatments that overcome these hidden barriers,” said Muir.

Block the effect of the metabolite

The research team now strives to discover why phosphoethanolamine accumulates in tumors and develop strategies to block its effects on immune cells.

Delgoff added: “The future of this project is to determine whether phosphoethanolamine could be a biomarker of the tumor load or even an immune suppression induced by the tumor, which could help us determine who could respond to immune therapies for cancer.”

He noted that “the team is also interested in designing new generation therapeutic strategies to reduce phosphoethanolamine levels in tumors in order to limit immunosuppression and stimulate immunotherapy”.

“We are really delighted with this, because it gives us a potential way to intervene and improve the function of T lymphocytes in the fight against tumors,” said Muir.

Additional authors include Yupeng Wang of Tsinghua Medical School, Beijing, China; Benjamin Cameron, Emerson Schoedel, William Gunn, Drew Wilfahrt, Bingxian Xie, Ronal Peralta, Dayana Rivadeneira of the University of Pittsburgh, Pittsburgh; Patrick Jonker, Konstantinos Lontos, Chufan Cai, Roya Amini Tabrizi and Hardik Shah from the University of Chicago, Chicago.