Research by a Harvard Medical School (HMS)-led research team has uncovered a new mechanism by which obesity can interfere with the immune system’s ability to fight cancer. Their studies demonstrated how, in tumor-bearing mice fed a high-fat diet, cancer cells reprogram their metabolism in response to the increased fat availability, so they can better consume energy-rich fat molecules, which then deprives tumor-killing T cells of fuel and accelerates tumor growth. The cancer cells effectively outcompete the immune cells in the battle for fuel, leading to reduced numbers and activity of CD8+ T cells in the tumor microenvironment (TME). Because CD8+ T cells are the main weapon used by immunotherapies that activate the immune system against cancer, the study results could point to potential new strategies for improving these treatment approaches.
“Cancer immunotherapies are making an enormous impact on patients’ lives, but they do not benefit everyone,” said Arlene Sharpe, MD, PhD, the HMS George Fabyan professor of comparative pathology and chair of the department of immunology in the Blavatnik Institute. Sharpe is co-senior author of the team’s published paper in Cell. “We now know there is a metabolic tug-of-war between T cells and tumor cells that changes with obesity. Our study provides a roadmap to explore this interplay, which can help us to start thinking about cancer immunotherapies and combination therapies in new ways.”
The team reported on its findings in a paper titled, “Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity.”
Obesity has been linked to an increased risk for over a dozen different types of cancer, as well as worse prognosis and survival. And while overall cancer rates have declined in the United States over the last decade, rates are rising for several obesity-related cancers, the researchers wrote. “Of cancers in patients >30 years of age in the United States, ~5% and 10% are attributable to excess body weight in men and women, respectively.”
Over the years, scientists have identified obesity-related processes that drive tumor growth, such as metabolic changes and chronic inflammation, but a detailed understanding of the interplay between obesity and cancer has remained elusive. And, as they pointed out, “It has not yet been reported how changes in systemic metabolism induced by obesity affect immune cells in the local tumor microenvironment.”
Sharpe and colleagues set out to investigate the effects of obesity in mouse models of different types of cancer, including colorectal, breast, melanoma and lung. Led by study co-first authors Alison Ringel and Jefte Drijvers, the team studied mice that were fed either a normal diet, or a high-fat diet (HFD), which led to increased body weight and other obesity-related changes. They then looked at different cell types and molecules inside and around tumors.
The researchers found that tumors grew much more rapidly in animals on high-fat diets compared with tumor grown in mice fed a normal diet. 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 that can target and kill cancer cells. Diet did not affect tumor growth rate if CD8+ T cells were eliminated experimentally in mice. Strikingly, 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. But when these cells were isolated and grown in a lab, they had normal activity, suggesting that something in the tumor had impaired CD8+ cell function.
The team 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 prompted 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 of this essential fuel. Interestingly, blocking this fat-related metabolic reprogramming significantly reduced tumor volume in mice on high-fat diets.
Thus, adaptive metabolic plasticity in tumors with obesity instigates a tug of war in the TME between tumor cells and CD8+ T cells for beneficial fatty acids,” the authors noted. “We find that tumor and CD8+ T cells display distinct metabolic adaptations to obesity. Tumor cells increase fat uptake with HFD, whereas tumor-infiltrating CD8+ T cells do not. These differential adaptations lead to altered fatty acid partitioning in HFD tumors, impairing CD8+ T cell infiltration and function.”
“Putting the same tumor in obese and nonobese settings reveals that cancer cells rewire their metabolism in response to a high fat diet,” said Marcia Haigis, PhD, professor of cell biology in the Blavatnik Institute at HMS and co-senior 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 needs to be better understood given the obesity epidemic in our society.”
“The paradoxical depletion of fatty acids was one of the most surprising findings of this study,” said Ringel, a postdoctoral fellow in the Haigis lab. “It really blew us away and it was the launch pad for our analyses. That obesity and whole-body metabolism can change how different cells in tumors utilize fuel was an exciting discovery, and our metabolic atlas now allows us to dissect and better understand these processes.”
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.
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 team also analyzed human tumor databases and found that low PHD3 expression was associated with immunologically “cold” tumors, defined by fewer numbers of immune cells. “Analysis of human cancers reveals similar transcriptional changes in CD8+ T cell markers, suggesting interventions that exploit metabolism to improve cancer immunotherapy,” they wrote. This association suggested that tumor fat metabolism plays a role in human disease, and that obesity reduces antitumor immunity in multiple cancer types, the authors said.
“The current study provides insight into the immunometabolic landscape within tumors at single-cell resolution,” the authors concluded. “Our studies reveal that tumor metabolism may significantly differ in a lean versus an obese setting, and that dietary stress may amplify the metabolic tug of war in tumors with a direct effect on the local function of CD8+ T cells.”
“CD8+ T cells are the central focus of many promising precision cancer therapies, including vaccines and cell therapies such as CAR-T,” Sharpe commented. “These approaches need T cells to have sufficient 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 for studying this dynamic and determining mechanisms that prevent T cells from functioning as they should.”
More broadly, the results serve as a foundation for efforts to better understand how obesity affects cancer and the impact of patient metabolism on therapeutic outcomes, the authors said. 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, the scientists said. And while the team acknowledged some limitations of their study, they concluded, “Our data determine conclusively that an individual’s systemic metabolism can transmit signals to the TME … An improved understanding of how systemic metabolism affects nutrient partitioning and immune function in the TME may have implications for therapeutic interventions targeting cancer metabolism and/or antitumor immunity with impacts on precision medicine and future patient care.”
“We’re interested in identifying pathways that we could use as potential targets to prevent cancer growth and to increase immune antitumor function,” Haigis said. “Our study provides a high-resolution metabolic atlas to mine for insights into obesity, tumor immunity, and the crosstalk and competition between immune and tumor cells. There are likely many other cell types involved and many more pathways to be explored.”