Harvard Medical School Confirms: Obesity Suppresses Immune Cells and Accelerates Tumor Growth

In today’s society, with the development of economy and the improvement of living standard, obesity has become a major public health problem all over the world.
According to the World Health Organization (WHO), nearly 2 billion people around the world are overweight or obese, and the global obesity rate nearly tripled from 1975 to 2016, causing 2.8 million deaths each year.
In fact, obesity is not only a feature, but also a disease. People with obesity are not only inconvenient to live, but also more prone to metabolic diseases and cardiovascular and cerebrovascular diseases. In addition, many studies have shown that obesity is associated with increased risk of more than ten kinds of cancer and reduced prognosis and survival rate.
Although China is not the country with the highest percentage of obese people, it has become the world’s most obese country in recent years due to its large population base.
For years, scientists have established that metabolic changes and chronic inflammation caused by obesity drive tumor growth, but the interaction between obesity and cancer has remained elusive.
On December 9, 2020, researchers from Harvard Medical School and other institutions published a paper in the international leading academic journal Cell entitled:
Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress anti-tumor Immunity. Abstract: Obesity affects the Metabolism of Tumor Microenvironment, thereby inhibiting anti-tumor Immunity.
The study showed that obesity reduced the number and antitumor activity of CD8+T cells, an important immune cell in tumors.
This is because cancer cells reprogram their metabolism in response to the increase in fat, making them better able to gobble up energy-rich fat molecules, depriving T cells of their energy supply and accelerating tumor growth.
More importantly, the research team discovered a protein called PHD3, which can inhibit excessive fat metabolism, and overexpression of PHD3 can effectively reverse the inhibition of tumor immune cells caused by high-fat diet, which is expected to become a new target for cancer treatment.
Definition of obesity
BMI, also known as body mass index, is a commonly used international standard to measure the degree of fat and health of a person.
BMI = weight (Kg) divided by height squared (m2). A BMI greater than 25 is considered overweight, while a BMI greater than 30 is considered obese.
Obesity leads to an undersupply of energy for T cells in tumors
To reveal the effect of obesity on cancer, the team studied mouse models with different cancer types, showing that a high-fat diet leads to obesity in mice, and that high-fat diet-induced obesity damages CD8+T cells in the tumor microenvironment and accelerates tumor growth.
Further experiments showed that diet-related differences in tumor growth were particularly dependent on CD8+T cell activity.
If CD8+T cells were eliminated experimentally in mice, diet did not affect the rate of tumor growth.
Surprisingly, the high-fat diet reduced the presence of CD8+T cells in the tumor microenvironment without reducing CD8+T cells in other parts of the body.
The remaining CD8+T cells in tumors are less robust, divide more slowly, and show signs of reduced activity.
But when the cells were isolated and grown under laboratory conditions, they showed normal activity, suggesting that something in the tumor was impelling the CD8+T cells.
Specifically, on a high-fat diet, cancer cells are able to reprogram their metabolism to increase fat uptake and use, while CD8+T cells are unable to, ultimately resulting in the depletion of certain fatty acids in the tumor microenvironment, rendering CD8+T cells unable to obtain this essential energy source.
“The abnormal consumption of fatty acids is one of the most surprising findings of this study,” said Alison E. Ringel, the study’s lead author. “It shows that obesity can change the way different cells in a tumor use their energy sources, which is both surprising and exciting.”
Identify potential therapeutic targets
Next, the team identified diet-related changes in metabolic pathways in tumor cells and immune cells in the tumor microenvironment using several different methods, including single-cell gene expression analysis, large-scale protein analysis, and high-resolution imaging.
Of particular interest in these metabolic changes was PHD3, which inhibits excessive fatty acid metabolism in normal cells, while the team found that PHD3 expression was significantly reduced in cancer cells in an obese environment.
The team overexpressed PHD3 in cancer cells, resulting in a decrease in the ability of the tumor cells in obese mice to metabolize fat, an increase in free fatty acids in the tumor microenvironment, and, more importantly, a recovery in the number of CD8+T cells in the tumor.
The cyan is tumor tissue and the red is CD8+T cells
Overall, the study found and confirmed that obesity reduces the number and antitumor activity of an important immune cell called CD8+T cells within tumors.
This is because cancer cells reprogram their metabolism in response to the increase in fat, making them better able to gobble up energy-rich fat molecules, depriving T cells of their energy supply and accelerating tumor growth.
More importantly, the research team discovered a protein called PHD3, which can inhibit excessive fat metabolism, and overexpression of PHD3 can effectively reverse the inhibition of tumor immune cells caused by high-fat diet, which is expected to become a new target for cancer treatment.
In recent years, the development of cancer immunotherapy is greatly affecting the lives of cancer patients. However, cancer immunotherapy does not benefit everyone.
The study suggests that there is a metabolic tug of war between T cells and tumor cells, and who is dominant changes with obesity.
This could help scientists start thinking about cancer immunotherapies and combination therapies.
These results also lay the foundation for a better understanding of how obesity affects cancer and how a patient’s metabolism affects treatment outcomes.