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Obesity impairs immune cell function and accelerates tumor growth

The high-fat diet causes cancer cells to reconfigure metabolism and increase fat intake, while cancer cells compete with immune cells for fuel, affecting immune function within tumors, according to a study from Harvard University published in the journal ‘Cell’.

Obesity has been linked to an increased risk of more than a dozen different types of cancer, as well as a 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 detailed understanding of the interaction between obesity and cancer remains elusive.

Now, in a study in mice, Harvard Medical School researchers have discovered a new piece to this puzzle, with surprising implications for cancer immunotherapy: Obesity allows cancer cells to outcompete the immune cells they kill. tumors in a battle for fuel.

In their report, the research team shows that a high-fat diet reduces the number and antitumor activity of CD8 + T cells, a fundamental type of immune cell, within tumors. This occurs because cancer cells reprogram their metabolism in response to increased availability of fat to better devour energy-rich fat molecules, starving T cells of fuel and accelerating tumor growth.

“Putting the same tumor in obese and non-obese settings reveals that cancer cells reconfigure their metabolism in response to a high-fat diet,” explains Marcia Haigis, professor of cell biology at HMS’s Blavatnik Institute and co-lead 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 should 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 to improve these therapies.

“Cancer immunotherapies are having a huge impact on the lives of patients, but they are not benefiting everyone,” recalls co-lead author Arlene Sharpe, HMS George Fabyan professor of comparative pathology and chair of the Department of Immunology at the Blavatnik Institute. – We now know that there is a metabolic tug of war between T cells and tumor cells that changes with obesity. Our study provides a roadmap for exploring this interaction, which may help us start thinking about cancer immunotherapies and combination therapies in new ways. “

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

The researchers found that tumors grew much faster in animals on high-fat diets compared to those on normal diets. But this occurred only in cancers that are immunogenic, which may contain a large number of immune cells, are more easily recognized by the immune system, and are more likely to elicit an immune response.

The experiments revealed that diet-related differences in tumor growth were specifically dependent on the activity of CD8 + T cells, immune cells that can attack and destroy cancer cells. Diet did not affect tumor growth rate if CD8 + T cells were experimentally killed in mice.

Surprisingly, high-fat diets reduced the presence of CD8 + T cells in the tumor microenvironment, but not in other parts of the body. Those that remained in the tumor were less strong: they divided more slowly and had markers of decreased activity. But when these cells were isolated and grown in a laboratory, they had normal activity, suggesting that something in the tumor affected the function of these cells.

The team also encountered an apparent paradox. In obese animals, the tumor microenvironment was depleted of key free fatty acids, an important source of cellular fuel, although the rest of the body was enriched in fat, as expected in obesity.

These clues led the researchers to produce a comprehensive atlas of the metabolic profiles of different cell types in tumors under conditions of a normal, high-fat diet.

The analyzes revealed that cancer cells adapted in response to changes in fat availability. On a high-fat diet, cancer cells were able to reprogram their metabolism to increase fat absorption and utilization, while CD8 + T cells did not. This ultimately depleted the tumor microenvironment of certain fatty acids, leaving T cells starving for this essential fuel.

“The paradoxical depletion of fatty acids was one of the most surprising findings of this study. It really surprised us and was the launching pad for our analyzes,” acknowledges Ringel, a postdoctoral fellow in Haigis’ lab. “Obesity and whole-body metabolism can change the way different tumor cells use fuel was an exciting discovery, and our metabolic atlas now allows us to better analyze and understand these processes. “

Through several different approaches, including single-cell gene expression analysis, large-scale protein studies, and high-resolution imaging, the team identified numerous diet-related changes in the metabolic pathways of both cancer and immune cells in the microenvironment. of the tumor.

More generally, the results serve as the basis for efforts to better understand how obesity affects cancer and the impact of the patient’s metabolism on therapeutic outcomes, the authors said. While it is too early to know if PHD3 is the best therapeutic target, the findings open the door to new strategies to fight cancer through its metabolic vulnerabilities, they note.

“We are interested in identifying pathways that we can use as potential targets to prevent cancer growth and increase antitumor immune function,” explains Haigis. “Our study provides a high-resolution metabolic atlas to obtain information on obesity, tumor immunity and crosstalk and competition between immune and tumor cells. There are likely many other cell types involved and many more avenues to explore. “

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