Obesity has long been linked to over a dozen types of cancer, as well as worsened outcomes and morbidity, and researchers at Harvard Medical School have identified one mechanism by which this heightened risk might be achieved.
 
In a new study using mouse models of cancer, which was published in the journal Cell, researchers found that exposing mice to a high-fat diet, inducing obesity, caused the cancer cells to outcompete critical CD8+T immune cells with anti-tumor properties in a battle for fuel.
 
“Putting the same tumor in obese and non-obese settings reveals that cancer cells can rewire their metabolism in response to a high fat diet,” Marcia Haigis, professor of cell biology in the Blavatnik Institute at Harvard Medical School and co-senior author of the study, said. “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.”
 
By blocking a fat-related metabolic reprogramming of cancer cells, the team significantly reduced tumor volume in mice on high-fat diets. CD8+T cells are the most predominant tool used in cancer immunotherapies that activate the immune system against cancer, suggesting that there may be new strategies for improving immunotherapies in obese populations.
 
“Cancer immunotherapies are making an enormous impact on patients’ lives, but they do not benefit everyone,” co-senior author Arlene Sharpe, the HMS George Fabyan Professor of Comparative Pathology and chair of the Department of Immunology in the Blavatnik Institute, said. “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 research team investigated the effects of obesity on mouse models of colorectal, breast, melanoma, and lung cancers, in which outcomes of both normal and high-fat diets were assessed. Part of that investigation involved examining the cell types and molecules inside of and around tumors, referred to as the tumor microenvironment.
 
Tumors made up of cancer types that are immunogenic (containing high numbers of immune cells) grew much more rapidly in animals on high-fat diets compared to normal diets. Immunogenic types of tumors are recognized more easily by the immune system and are more likely to provoke an immune response, the authors said.
 
High-fat diets reduced the presence of CD8+T cells in the tumor microenvironment, but not elsewhere in the body, the researchers found. Those cells which remained in the tumor also divided more slowly and had markers of decreased activity, but their activity normalized when the cells were removed from the tumors, suggesting that somehow the tumor impaired these cells’ function.
 
Interestingly, the team also found that 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, which is typical of obesity.
 
While CD8+ T cells couldn’t adapt in response to changes in fat availability, the tumor cells were able to adapt, leaving the T cells starved for essential fuel in the presence of the tumors.
 
“The paradoxical depletion of fatty acids was one of the most surprising findings of this study. It really blew us away and it was the launch pad for our analyses,” Allison Ringel, a co-author of the study, said. “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.”
 
Dietary Change Induction Showed Promise
The team identified a number of diet-related changes to metabolic pathways of both cancer and immune cells in the tumor microenvironment through single-cell gene expression analyses, large-scale protein surveys, and high-resolution imaging.
 
Cancer cells had a much lower expression of PHD3 compared to in a normal environment – PHD3 is a protein which acts as a brake on excessive fat metabolism. By forcing tumor cells to over-express this protein, they diminished the tumor’s ability to take up fat in obese mice. This also restored the availability of key free fatty acids in the tumor microenvironment. On the whole, increased PHD3 expression reversed the negative effects of a high-fat diet on immune cell function in tumors. Also of interest, tumor growth obese mice lacking CD8+ T cells was unaffected by differences in the expression of this protein.
 
This phenomenon has been previously observed in human tumors, as well – human tumor databases have shown that low PHD3 expression was associated with immunologically “cold” tumors, defined by fewer numbers of immune cells, the researchers said.
 
Takeaways
“CD8+ T cells are the central focus of many promising precision cancer therapies, including vaccines and cell therapies such as CAR-T,” Sharpe said. “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, this research demonstrates that patient metabolism has an impact on cancer and immunotherapies. While PHD3 isn’t necessarily the best therapeutic target, the findings show that could be one of many new strategies to combat cancer through its metabolic vulnerabilities, the authors 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,” Haigis said.