Obesity has been linked to increased risk for over a dozen different types of cancer, as well as worse prognosis and survival. 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.
Now, in a study in mice,
Harvard Medical School researchers have uncovered a new piece of this puzzle,
with surprising implications for cancer immunotherapy: Obesity allows cancer
cells to outcompete tumor-killing immune cells in a battle for fuel.
Reporting in Cell on
Dec. 9, the research team shows that a high-fat diet reduces 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.
“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, 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 team found that blocking
this fat-related metabolic reprogramming significantly reduced tumor volume in
mice on high-fat diets. Because 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.
“Cancer immunotherapies are
making an enormous impact on patients’ lives, but they do not benefit
everyone,” said co-senior author Arlene Sharpe, the HMS George Fabyan Professor
of Comparative Pathology and chair of the Department of Immunology in the
Blavatnik Institute.
“We now know there is a
metabolic tug-of-war between T cells and tumor cells that changes with
obesity,” Sharpe said. “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.”
Haigis, Sharpe and colleagues
investigated the effects of obesity on 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 gave mice normal or high-fat
diets, the latter leading to increased body weight and other obesity-related
changes. They then looked at different cell types and molecules inside and
around tumors, together called the tumor microenvironment.
Fatty
paradox
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.
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
something in the tumor impaired these cells’ 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 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.
“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,” said Ringel, a
postdoctoral fellow in the Haigis lab. “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.”
Hot and cold
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. 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.
“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, 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, they said.
“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.”
Source: https://hms.harvard.edu/news/obesity-cancer
Journal article: https://www.cell.com/cell/fulltext/S0092-8674(20)31526-9
Image: Obesity initiates a
tug-of-war between tumor (green and brown) and immune cells (white) for
critical fuels. Tumors outcompete immune cells in high-fat diet environments
(left) compared to normal diet (right). Illustration: Shraddha M. Nayak and
Janet Iwasa
No comments:
Post a Comment