High-fat diet causes cancer cells to rewire metabolism, increase fat consumption

Obesity allows cancer cells to outcompete tumor-killing immune cells in a battle for fuel, according to a new study by researchers at Harvard Medical School published in the journal Cell.

In the study, the researchers showed that a high-fat diet reduced 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, according to the study.

The researchers found that blocking this fat-related metabolic reprogramming significantly reduced tumor volume in mice on high-fat diets. Since 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, the researchers said.

The researchers found that tumors grew much more rapidly in animals on high-fat diets compared to those on normal diets. But this occurred only in cancer types that are immunogenic, which can contain high numbers of immune cells; are more easily recognized by the immune system; and are more likely to provoke an immune response.

Experiments revealed that diet-related differences in tumor growth depended specifically on the activity of CD8+ T cells, immune cells that can target and kill cancer cells. Diet did not affect tumor growth rate if CD8+ T cells were eliminated experimentally in mice, the researchers said.

Additionally, high-fat diets reduced the presence of CD8+ T cells in the tumor microenvironment, but not elsewhere in the body. Those remaining in the tumor were less robust--they divided more slowly and had markers of decreased activity. When these cells were isolated and grown in a lab, they had normal activity, suggesting something in the tumor impaired these cells' function, according to the study.

The researchers also encountered an apparent paradox. In obese animals, the tumor microenvironment was depleted of key free fatty acids, a major cellular fuel source, even though the rest of the body was enriched in fats, as expected in obesity. These clues pushed the researchers to craft a comprehensive atlas of the metabolic profiles of different cell types in tumors under normal and high-fat diet conditions.

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

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

Of particular interest was PHD3, a protein that in normal cells has been shown to act as a brake on excessive fat metabolism. Cancer cells in an obese environment had significantly lower expression of PHD3 compared to in a normal environment. When the researchers forced tumor cells to overexpress PHD, they found that this diminished a tumor's ability to take up fat in obese mice. It also restored the availability of key free fatty acids in the tumor microenvironment, according to the study.

Increased PHD3 expression largely reversed the negative effects of a high-fat diet on immune cell function in tumors. Tumors with high PHD3 grew slower in obese mice compared to tumors with low PHD3. This was a direct result of increased CD8+ T cell activity. In obese mice lacking CD8+ T cells, tumor growth was unaffected by differences in PHD3 expression.

The researchers also analyzed human tumor databases and found that low PHD3 expression was associated with immunologically "cold" tumors, defined by fewer numbers of immune cells. This association suggested that tumor fat metabolism plays a role in human disease, and that obesity reduces antitumor immunity in multiple cancer types, the researchers said.

More broadly, the researchers said the results serve as a foundation for efforts to better understand how obesity affects cancer and the impact of patient metabolism on therapeutic outcomes. While it's too early to tell if PHD3 is the best therapeutic target, the findings open the door for new strategies to combat cancer through its metabolic vulnerabilities, according to the researchers.