By Michael Irving; December 09, 2020
Levels of CD8+ T cells (red) in tumors (cyan) appear to be higher in mice on lower-fat diets (top row) than those on high-fat diets (bottom row)Ringel et al
Obesity has long been linked to cancer, but the complete picture still eludes scientists. Now, a new study from Harvard highlights some missing pieces of the puzzle, finding that cancer cells can use the higher fat availability to starve immune cells of fuel and prevent them from targeting tumors.
High-fat diets are known to increase the risk for many types of cancer, and reduce treatment outcomes and survival rates. For instance, previous studies have found that obesity may promote metastasis in otherwise benign cancers, and fatty tissues can provide “hideouts” for cancer stem cells, allowing them to come roaring back after chemotherapy. But it’s not that simple either – paradoxically, obesity appears to improve outcomes for some types of cancer treatments.
In the new study, Harvard researchers found that high-fat diets seem to reduce the amount of CD8+ T cells, as well as their cancer-fighting abilities. When fat is more readily available, tumors will rewire their metabolism to gobble it up. The high energy content accelerates their growth, while at the same time depriving T cells of fuel which they would otherwise use to fight cancer.
“We now know there is a metabolic tug-of-war between T cells and tumor cells that changes with obesity,” says Arlene Sharpe, co-senior author of the study. “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 studied this complex relationship in mice with different types of cancer, by feeding some groups high-fat diets and comparing the microenvironments around their tumors to those of mice eating normal diets. They found that tumors grew much faster in the obese mice, but interestingly, that only applied to mice with immunogenic cancers – those that the immune system responds to more readily.
The researchers also noticed that in obese mice, the tumor microenvironment contained far fewer free fatty acids, even though their numbers were very high throughout the rest of the body. This led the team to discover that the cancer cells were increasing their fat uptake, leaving none for the CD8+ T cells.
“The paradoxical depletion of fatty acids was one of the most surprising findings of this study,” says Alison Ringel, co-first author of the study. “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.”
In other tests, when the team eliminated CD8+ T cells from mice, their diet no longer affected the rate of tumor growth.
Through further work, the researchers zeroed in on a protein called PHD3, which in normal cells slows down fat metabolism. PHD3 levels were found to be significantly lower in cancer cells in obese environments than otherwise, and when the scientists overexpressed the protein in tumors they grew more slowly and couldn’t take up as much fat.
All up, the researchers say that the new discoveries could help improve cancer immunotherapy. After all, CD8+ T cells are used in CAR-T cell therapy, where samples of a patient’s immune cells are removed, supercharged against cancer and reintroduced to the body. PHD3, or another related protein, could become a new therapeutic target. The find could also help personalize other cancer therapies for obese patients.
The research was published in the journal Cell.
Source: Harvard
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