Obesity has become a worldwide "epidemic", one of the most important public health problems in the 21st century , and a major risk factor for several chronic diseases including diabetes, cardiovascular disease and various cancers. This disease, once seen as only appearing in high-income countries, is now on the rise in low- and middle-income countries.
At present, obesity has been confirmed to be associated with increased risk of dozens of cancers (lung cancer, liver cancer, pancreatic cancer, thyroid cancer, cervical cancer, breast cancer, colorectal cancer, etc.), as well as worse prognosis and survival rates.
Over the years, scientists have also discovered risk factors related to obesity that can lead to tumor growth, such as metabolic changes and chronic inflammation. However, the detailed process of the interaction between obesity and cancer remains unclear.
Now, researchers from Harvard Medical School and their collaborators have revealed this answer for us in a new study: Obesity caused by a high-fat diet makes cancer cells compete with immune cells for metabolic fuel. Win .
Researchers have found that a high-fat diet reduces the number and anti-tumor activity of CD8+ T cells (a type that can kill cancer cells, virus-infected cells, and other damaged immune cells) in tumors. This is because cancer cells will re-design their metabolic mechanism to adapt to the increasing fat, so as to better snatch the energy-rich fat molecules from T cells, and accelerate the tumor’s growth while inhibiting T cell metabolism. Grow.
Figure｜High-fat diet can interfere with the metabolism of CD8 + T cells, thereby impairing their anti-tumor immunity (Source: Cell)
Figure | Comparison of CD8+ T cell (red) content in tumor cells (blue-green). Compared with the tumors of obese mice (bottom), the tumors of non-obese mice (top) contained more CD8+ T cells (source: Cell)
At the same time, they found that the increased expression of PHD3 (a protein that has been shown to inhibit excessive fat metabolism in normal cells) can largely reverse the negative effects of high-fat diet on tumor immune cell function, and may have the potential to become the future Targets for treatment of a variety of cancer diseases.
Related papers entitled "Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity" were published online in the scientific journal Cell.
(Source: Cell)
Marcia Haigis, one of the authors of the paper and a professor of cell biology at the Blavatnik Institute at Harvard Medical School, said that the results of this study indicate that a therapy that may be effective in one environment may no longer be effective in another environment. Obesity is currently widespread worldwide, and since CD8+ T cells are the "main weapon" in immunotherapy, they can activate the immune system to fight cancer. Therefore, this research discovery has very important theoretical value and proposes new strategies for improving this type of immunotherapy.
Obesity is huge and should not be underestimated
Obesity can lead to various serious health consequences, such as cardiovascular disease (mainly heart disease and stroke), type 2 diabetes, osteoarthritis and other musculoskeletal disorders, and some cancers (endometrial cancer, breast cancer, and colon cancer). These diseases can cause severe disability and even premature death in obese people.
Data from the World Health Organization (WHO) show that since 1975, the number of obese people in the world has nearly tripled; in 2016, more than 1.9 billion adults aged 18 and over were overweight, of which more than 650 million were obese. There are 340 million children and adolescents aged 5-19 who are overweight or obese. The prevalence of overweight and obesity among children and adolescents aged 5-19 has risen from only 4% in 1975 to over 18% in 2016. The rise is similar, with 18% of girls and 19% of boys overweight; in most countries in the world, the number of deaths from overweight and obesity is greater than the number of deaths from underweight; in 2019, the number of children under 5 who are overweight or obese It has reached about 38 million, and nearly half of them live in Asia.
(Source: Pixabay)
On the same day, another study by Dr. Tom Norris (Tom Norris) and his collaborators from Loughborough University in the United Kingdom also revealed the hazards of obesity to our health.
Researchers analyzed the body mass index (BMI) and risk factors of cardiovascular and metabolic diseases from 20,746 subjects aged 10-40.
The results showed that the longer the duration of obesity, the worse the values related to cardiovascular and metabolic disease risk factors (blood pressure, blood sugar, cholesterol, etc.) , especially glycosylated hemoglobin (a diagnostic test for diabetes). Compared with people without a history of obesity, people with a history of obesity less than 5 years have a 5% higher glycated hemoglobin value, and for those with a history of 20-30 years of obesity, this figure is even more alarming. 20% of it.
It can be seen that the harm of obesity is far beyond our imagination.
In recent years, as the incidence of obesity-related cancers continues to rise, studying and discovering the relationship between obesity and cancer is crucial for future cancer prevention and treatment research.
Obesity has always been regarded as the main risk factor for cancer. Previous studies on obesity and cancer have mainly focused on the intrinsic tumor effect or the endocrine tumor cell regulation axis. However, how does the difference in body metabolism change the tumor microenvironment and affect the anti-tumor immunity? Not sure.
Uncover the "action" of obesity and cancer
In this work, in order to reveal the effect of obesity on mice with different types of cancer (lung cancer, breast cancer, colorectal cancer, and melanoma, etc.), the researchers provided different groups of mice with a high-fat diet. -fat diet (HFD) and control diet (control diet, CD) , among which high-fat diet can cause obesity symptoms and other obesity-related changes in mice, and observe the tumor microenvironment (including the tumor inside and its surrounding environment) Of different cell types and molecules.
The results show that obesity induced by a high-fat diet can impair the function of CD8+ T cells in the tumor microenvironment of mice, accelerate tumor growth, and block this fat-related metabolism. Re-designing can significantly reduce the passive acceptance of a high-fat diet. The tumor volume in mice improves anti-tumor immunity.
Figure | High-fat diet inhibits the proliferation and activity of CD8+ T cells in tumors. A. Schematic diagram of experimental setup, mouse colon cancer model MC38; BL. Flow cytometry analysis (used to count and sort tiny particles suspended in fluid) analysis results; M, N. Quantify CD8+ tumor infiltration in tumors GZMB expression in lymphocytes (CD8+ TILs). (Source: Cell)
One of the authors of the paper, "George Fabyan" Professor of Comparative Pathology at Harvard Medical School, and Director of the Department of Immunology at the Blavatnik Institute, Arlene Sharpe, said that although cancer immunotherapy has had a huge impact on the lives of patients, not everyone can learn from it. Benefit.
" We now know that there is a metabolic tug-of-war (metabolic tug-of-war) between T cells and cancer cells. Whoever wins will change with the degree of obesity of the body. Our research is to explore this. Interaction provides a roadmap to help us think about cancer immunotherapy and combination therapies in new ways."
Since previous analysis of human cancers revealed similar transcriptional changes in CD8 + T cell markers, it is expected that in the future, an intervention that uses metabolism to improve cancer immunotherapy will be developed.
In addition, the researchers also found that compared with animals on a normal diet, tumors in animals on a high-fat diet grew faster, but this only occurred in immunogenic tumors. These tumors may contain a large number of immune cells and are more likely to be affected. Recognition by the immune system is more likely to trigger an immune response. Experiments have shown that diet-related tumor growth differences are particularly dependent on the activity of CD8+ T cells. However, if the CD8+ T cells in the mice are eliminated in the experiment, the diet has no effect on tumor growth.
Even more surprising is that the high-fat diet only reduced the number of CD8+ T cells in the tumor microenvironment, while the number of CD8+ T cells in other parts of the body did not decrease.
Moreover, those CD8+ T cells remaining in the tumor microenvironment, although their activity is significantly reduced, when these cells are isolated and grown in the laboratory, they will have normal activity again. This indicates that something in the tumor is impairing the function of CD8+ T cells.
The researchers also found a very obvious contradiction : in obese animals, although other parts are still rich in fat, the key free fatty acids in the tumor microenvironment (the main fuel source for cells) have been exhausted.
These "clues" prompted the researchers to draw a metabolic atlas of different cell types in tumors under normal and high-fat diets.
Analysis shows that cancer cells respond to changes in body fat content. Under a high-fat diet, in order to increase the intake and utilization of fat, cancer cells will re-design their metabolic functions, but CD8+ T cells cannot. This causes certain fatty acids in the tumor microenvironment to be depleted, and T cells are lacking. This necessary fuel reduces the activity.
Alison Ringel, one of the authors of the paper and a postdoctoral fellow in Haigis Lab, said that this "contradictory" consumption of fatty acids is one of the most surprising findings of this study. "Obesity and systemic metabolism can change the way different cells in tumors use fuel. This is a very exciting discovery. Our metabolic map allows us to dissect and better understand these processes."
A potential cancer treatment target
Through methods such as single-cell gene expression analysis, large-scale protein surveys, and high-resolution imaging, researchers have identified changes in many diet-related metabolic pathways in cancer cells and immune cells in the tumor microenvironment.
A particularly exciting discovery is PHD3 , a protein that has been shown to inhibit excessive fat metabolism in normal cells. Researchers found that cancer cells in an obese environment have significantly lower PHD3 expression compared to normal conditions. At the same time, when they "forced" tumor cells to overexpress PHD, the ability of tumors to "grab" fat in obese mice was correspondingly reduced, and the key free fatty acid content in the tumor microenvironment also increased.
Figure | Increasing the expression of PHD3 in tumor cells can increase CD8+ T activity and inhibit tumor growth. (Source: Cell)
The increase in PHD3 expression largely reversed the negative impact of high-fat diet on tumor immune cell function. Compared with tumors with low PHD3 expression, tumors with high PHD3 expression grow more slowly in obese mice. This is a direct effect of the increase in CD8+ T cell activity. In obese mice lacking CD8+ T cells, differences in PHD3 expression did not affect tumor growth.
Researchers analyzed the human tumor databases and found that the low expression of PHD3 is related to "cold" tumor cells (smaller number of immune cells). This connection shows that tumor fat metabolism plays an important role in human diseases, and obesity reduces the body's anti-tumor immunity against many cancers.
"CD8+ T cells are the focus of many precision cancer therapies such as vaccine research and development, cell therapies (such as CAR-T). These methods require T cells to have enough energy to kill cancer cells, but at the same time, we don’t want tumors to have enough energy. The fuel to grow. Now, we have comprehensive data to study this dynamic and deterministic mechanism that prevents T cells from achieving their due function.” Sharpe explained.
The researchers said that this result lays the foundation for a better understanding of how obesity affects cancer and the impact of patient metabolism on treatment outcomes. Although PHD3 is currently not the best therapeutic target, this discovery opens the door to new strategies to fight cancer through its metabolic vulnerability.
"We can use these potential targets to prevent cancer and enhance immune and anti-tumor functions. Our research provides a high-resolution metabolic map to explore the effects on obesity, tumor immunity, and the interaction between immune cells and cancer cells. Competitive insights. In the future, there is more work to be explored." Haigis said.
In addition, this research also has certain limitations. The researchers said that although they revealed to a certain extent the proof of concept that the transcriptional changes in tumor cells of mice on a high-fat diet inhibited anti-tumor immunity, they did not prove that this was caused by increased fat oxidation in the MC38 cells of the mouse colon cancer model; Moreover, obesity caused by excessive diet is systemic, and PHD3 is only helping to increase the activity of CD8+ T cells and inhibit tumor growth. There are many other factors that may reduce the anti-tumor response of CD8+ T cells. Therefore, further research is needed for related work.
Take care of your mouth and open your legs
The root cause of obesity and overweight is the energy imbalance between calorie intake and calorie consumption.
With the gradual improvement of living standards, people’s intake of high-energy foods rich in fats and sugars continues to increase; moreover, more and more sedentary, changes in transportation, and the increase in urbanization have made us lack of physical activity. The problem is getting worse.
(Source: Pixabay)
Fortunately, obesity can be prevented. The World Health Organization recommends that fat consumption can be achieved by limiting the energy intake of total fat and converting saturated fat into unsaturated fat; at the same time, increase the consumption of fruits and vegetables, as well as legumes, whole grains and nuts; and limit Sugar intake; in addition, you can increase the amount of physical activity, usually at least 30 minutes of regular activity every day, but the activity intensity should be moderate.
It can be seen that managing your mouth and opening your legs is a good choice without any harm.
reference:
https://www.cell.com/cell/fulltext/S0092-8674(20)31526-9
https://www.who.int/topics/obesity/zh/
https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1003387