Cell heavy interpretation! Obesity impairs the molecular mechanisms of immune cell function and accelerates tumor growth!

December 21, 2020 / -- Obesity is associated with an increased risk of more than a dozen different types of cancer, as well as a direct correlation with a decrease in the prognostic and survival rates of patients.
years, scientists have identified obesity-related processes that drive tumor growth, such as metabolic changes and chronic inflammation, but they have not elaborated on the specific interactions between obesity and cancer.
In a recent study published in the international journal Cell entitled "Obesity Shapes Metabolism in The Tumorenvironment to Suppress Anti-Tumor Immunity," scientists from Harvard Medical School and others uncovered the puzzle by finding that obesity promotes cancer cells to beat the immune cells that kill tumors in the battle for energy. the
researchers say a high-fat diet reduces the number of CD8-plus T cells in tumors and anti-tumor activity, because cancer cells reprogram their metabolism to cope with an increased fat supply, better devouring energy-rich fat molecules, depriving T-cells of fuel and accelerating tumor growth.
Researcher Marcia Haigis says putting the same tumors in an obese and non-obese environment could reveal that cancer cells reordell their cell metabolism in response to a high-fat diet; the results suggest that treatments that may be effective in one environment may not be as effective in another, and that given the current prevalence of obesity in the population, further research may be needed.
Blocks fat-related metabolic reprogramming or significantly reduces tumor volume in mice on a high-fat diet, and since CD8-T cells are the primary weapon for immunotherapy to activate the host body's immune system against cancer, in this study, researchers propose new strategies to improve such therapies.
cancer immunotherapy can have a huge impact on the lives of cancer patients, but not every patient can benefit.
Now that researchers know that there is a metabolic tug-of-war between T-cells and tumor cells as obesity changes, this study may provide a roadmap for exploring this interaction, which may help us begin to think about the mechanisms of cancer immunotherapy and combination therapy in new ways.
photo source: Ringel et al, 2020, the researchers investigated the effects of obesity on mouse models of different types of cancer, including colorectal cancer, breast cancer, melanoma and lung cancer.
gave mice a normal or high-fat diet and then looked at the different cell types and molecular types present in the tumor micro-environment.
researchers found that tumors grow faster in animals on a high-fat diet than in animals on a normal diet, but this only occurs in immunogenic cancer types, which tend to contain high levels of immune cells and are more easily identified by the immune system and prone to an immune response.
results show that differences in tumor growth associated with diet are specifically dependent on the activity of CD8 plus T cells, which target and kill cancer cells, and if CD8 plus T cells can be eliminated experimentally in mice, diet may not affect tumor growth.
results showed that a high-fat diet reduced the presence of CD8-T cells (not other parts of the body) in the tumor micro-environment.
The cells that remain in the tumor appear to be less strong, divide more slowly and show signs of decreased activity, but when they are isolated and grow in the lab, they are normally active, suggesting that something in the tumor impairs the function of the cells.
In addition, the researchers found that in obese animals, the key free fatty acids in the tumor micro-environment may be depleted, and free fatty acids are the main source of cell fuel, even if the rest of the body is rich in fat.
these findings may help researchers map out the metabolic properties of different types of cells in tumors under normal and high-fat diets.
Cancer cells may adjust to changes in fat supply, and in a high-fat diet, cancer cells can reprogram their metabolism to increase fat intake and utilization, while CD8-T cells do not, which eventually suggests certain fatty acids in the tumor micro-environment, making T-cells hungry for this basic fuel.
researcher Ringel said the abnormal consumption of fatty acids was one of the study's most surprising findings: obesity and systemic metabolism can alter the way different cells in tumors use fuel, and the metabolic maps the researchers have mapped may help scientists better interpret these processes.
study, the researchers identified a variety of dietary-related changes in the response to metabolic paths in cancer cells and immune cells in the tumor micro-environment using a variety of techniques, including single-cell gene expression analysis.
Of particular concern is PHD3, a protein that has been shown to be a brake on excessive fat metabolism in normal cells, which significantly reduces the expression of PHD3 in cancer cells in an obese environment compared to normal environments, and when researchers drive tumor cells to overexploit PHD, they found that this may reduce the ability of tumors in obese mice to consume fat, while also restoring the availability of key free fatty acids in tumor micro-environments.
Increased expression of PHD3 significantly reverses the negative effects of a high-fat diet on immune cell function in tumors, while tumors with high levels of PHD3 grow more slowly in obese mice than tumors with low levels of PHD3, which may be a direct result of increased CD8-T cell activity, and tumor growth is not affected by differences in PHD3 expression in obese mice that lack CD8-T cells.
researchers also analyzed the human tumor database and found that the expression of low levels of PHD3 was directly related to immunologically "cold" tumors (a small number of immune cells), which may indicate that tumor fat metabolism plays a key role in the onset of human disease, and that obesity also reduces anti-tumor immunity for many types of cancer.
researcher Sharpe said CD8-plus T cells are at the heart of promising cancer therapies, including vaccines and cell therapies such as CAR-T, which require T-cells to have enough energy to kill cancer cells, but researchers don't want tumors to have fuel to grow, and now they have comprehensive data to study the dynamic changes and identify mechanisms that block the functioning of T-cells.
the results of this paper may help scientists better understand the molecular mechanisms of obesity that affect cancer and how patient metabolism affects the prognostication of the treatment.
while it's too early to judge PHD3 as the best therapeutic target, the findings may help researchers fight cancer by harnessing the metabolic susceptivity of cancer cells.
The researchers are very interested in identifying special path paths that they use as potential targets to develop anti-tumor functions that inhibit cancer growth and increase the immune anti-tumor function of host bodies, and this study provides a high-resolution metabolic map to dig deep into the association between obesity and tumor immunology, as well as the mechanisms of competition between immune cells and tumor cells, and perhaps other types of cells, which will need to be further explored by scientists.
() References: Alison E. Ringel, Jeffery M. Drijvers, Gregory J. Baker, et al. Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity, Cell (2020). DOI: 10.1016/j.cell.2020.11.009【2】Obesity impairs immune cell function, accelerates tumor growthby Harvard Medical School。