A high-fat diet allows cancer cells to compete with immune cells for fuel.

According to Harvard Medical School

Obesity is associated with an increased risk of more than a dozen different types of cancer, as well as a worse prognosis and survival. For years, scientists have identified obesity-related processes that promote tumor growth, such as metabolic changes and chronic inflammation, but a detailed understanding of the relationship The link between obesity and cancer remains elusive.

Now, in a mouse study, Harvard Medical School researchers have uncovered a new piece of the puzzle, with surprising implications for cancer immunotherapy: Obesity for cancer allowing cancer cells to outmaneuver tumor-killing immune cells in the fight for fuel.

Reporting in the journal Cell today, the team shows that a high-fat diet reduces the number and anti-tumor activity of CD8+ T cells, a type of immune cell important in the interior of cells. tumor. This happens because cancer cells reprogram their metabolism in response to increased fat availability in order to better absorb energy-rich fat molecules, taking away fuel. T cells and accelerate tumor growth.

“Putting the same tumor together in obese and non-obese individuals shows that cancer cells upregulate their metabolism in response to a high-fat diet. Marcia Haigis, Blavatnik Institute professor of cell biology at HMS and co-author of the study. “This finding suggests that a therapy that works in one setting may not be effective in another, which needs to be better understood in the context of obesity in our society.”

The team found that blocking this fat-related metabolic reprogramming significantly reduced tumor volume in mice on a high-fat diet. Because CD8+ T cells are the primary weapon used by immunotherapies to activate the immune system against cancer, the study results suggest new strategies to improve such therapies.

Co-author Arlene Sharpe, HMS George Fabyan Professor of Comparative Pathology and chair of the Department of Immunology at the Blavatnik Institute said: “Cancer immunotherapy is making a tremendous impact on patients’ lives, but They don’t benefit everyone.

“We now know that there is a metabolic battle between T cells and tumor cells that changes with obesity,” says Sharpe. “Our study provides an avenue to explore this interaction, which may help us start thinking about cancer immunotherapies and combination therapies in new ways.”

Haigis, Sharpe and colleagues studied the effects of obesity in mouse models of different types of cancer, including colorectal, breast, melanoma, and lung cancer. Led by study co-authors Alison Ringel and Jefte Drijvers, the team fed mice a normal or high-fat diet, the latter of which resulted in increased body weight and other changes associated related to obesity. They then looked at different types of cells and molecules in and around tumors, collectively known as the tumor microenvironment.

Fat paradox

The researchers found that tumors grew much faster in animals fed a high-fat diet than in animals fed a normal diet. But this only occurs in immunogenic cancers, which may contain many immune cells; more easily recognized by the immune system; and are more likely to induce an immune response.

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

Notably, a high-fat diet reduced the presence of CD8+ T cells in the tumor microenvironment, but not elsewhere in the body. The cells left in the tumor are less vigorous – they divide more slowly and show signs of decreased activity. But when these cells were isolated and grown in the lab, they still functioned normally, indicating that something in the tumor is impairing the function of these cells.

The team also encountered an obvious paradox. In obese animals, the tumor microenvironment is depleted of important free fatty acids, a major source of cellular fuel, although the rest of the body is enriched by fat, as expected in obese patients.

These clues prompted the researchers to create a comprehensive atlas of the metabolic profiles of different cell types in tumors under normal and high-fat eating conditions.

The analysis showed that the cancer cells had adapted to changes in fat availability. Following a high-fat diet, cancer cells can reprogram their metabolism to increase fat absorption and utilization, while CD8+ T cells cannot. This ultimately depletes the tumor microenvironment of certain fatty acids, starving the T cells of this essential fuel source.

“The paradoxical depletion of fatty acids is one of the most surprising findings of this study,” said Ringel, a PhD student at the Haigis lab. “Obesity and how whole body metabolism can change the way different cells in a tumor use fuel is an exciting discovery, and our metabolic atlas now allows us to dissect and better understand these processes.”

Hot and cold

Through a number of different approaches, including single-cell gene expression analysis, large-scale proteomics, and the use of high-resolution imaging, the team identified many related changes. to diet on the metabolic pathways of both cancer cells and immune cells in the tumor microenvironment.

Of particular interest is PHD3, a protein found in normal cells that has been shown to inhibit excessive fat metabolism. Cancer cells in the obese environment had a significantly lower presence of PHD3 than in the normal environment. When the researchers forced tumor cells to overexpress PHD, they found that this reduced the tumor’s ability to absorb fat in obese mice. It also restores the availability of important free fatty acids in the tumor microenvironment.

Increased PHD3 largely reversed the negative effects of a high-fat diet on immune cell function in tumors. Tumors with high PHD3 grew more slowly in obese mice than tumors with low PHD3. This is a direct result of increased CD8+ T cell activity. In mice that are obese and lack CD8+ T cells, tumor growth is not affected by PHD3 differentiation.

The team also analyzed human tumor databases and found that low PHD3 was associated with immunologically “cold” tumors, defined by a lower number of immune cells. This association suggests that tumor fat metabolism plays a role in human disease and that obesity reduces anti-tumor immunity in many types of cancer, the authors said.

“CD8+ T cells are at the heart of many promising and precise cancer therapies, including vaccines and cell therapies such as CAR-T,” said Sharpe. “These approaches need T cells to have enough energy to kill cancer cells, but at the same time we don’t want tumors to have fuel to grow. We now have amazingly comprehensive data to study this dynamic and identify a mechanism that prevents T cells from functioning as they should. “

And more broadly, this result serves as a foundation for efforts to better understand the extent to which obesity affects cancer and the impact of patient metabolism on treatment outcomes, said the authors. Although it is too early to say whether PHD3 is the best therapeutic target, these findings open the door to new strategies to fight cancer through its metabolic vulnerabilities. , they say.

“We are interested in identifying pathways that we can use as potential targets to suppress cancer growth and enhance anti-tumor immune function,” said Haigis. “Our study provides a high-resolution metabolic atlas to mine for insights into obesity, tumor immunity, and intercellular competition and linkages. immunity and tumors. And there will be many other cell types and related pathways to be discovered.”

References: Materials provided by Harvard Medical School.

Source: https://www.sciencedaily.com/releases/2020/12/201209115216.htm

Journal Reference:

1. Alison E. Ringel, Jefte M. Drijvers, Gregory J. Baker, Alessia Catozzi, Juan C. García-Cañaveras, Brandon M. Gassaway, Brian C. Miller, Vikram R. Juneja, Thao H. Nguyen, Shakchhi Joshi, Cong- Hui Yao, Haejin Yoon, Peter T. Sage, Martin W. LaFleur, Justin D. Trombley, Connor A. Jacobson, Zoltan Maliga, Steven P. Gygi, Peter K. Soger, Joshua D. Rabinowitz, Arlene H. Sharpe, Marcia C. Haigis. Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity. Cell, 2020; DOI: 10.1016/j.cell.2020.11.009

Author: Ngoc Khanh.

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