Cell: New target for cancer immunotherapy - PHD3

Obesity has been shown to be associated with an increased risk of more than 10 cancers, as well as poorer prognosmation and survival rates.
years, scientists have identified obesity-related processes that drive tumor growth, such as metabolic changes and chronic inflammation, but a detailed understanding of the interactions between obesity and cancer remains inadequate.
study, published in the journal Cell, scientists from Harvard Medical School have made a startling discovery: Obesity makes cancer cells compete with tumor-killing immune cells for fuel.
findings may have a crucial impact on cancer immunotherapy.
study revealed that a high-fat diet reduced the number of CD8-T cells in tumors and anti-tumor activity.
result is that cancer cells respond to increased fat reprogramming their metabolic procedures to better devour energy-rich fat molecules, depriving T cells of fuel and accelerating tumor growth.
and blocking this fat-related metabolic reprogramming can significantly reduce tumor volume in mice on a high-fat diet.
, professor of cell biology who led the study, said: "Putting the same tumors in an obese and non-obese environment reveals that cancer cells respond to a high-fat diet to change their metabolism.
considering the obesity epidemic in society, we need to better understand this finding.
specifically, in this study, Professor Haigis and his partners investigated the effects of obesity on mouse models of different types of cancer, including colorectal, breast, melanoma and lung cancer.
researchers gave mice a normal or high-fat diet, which can lead to weight gain and other obesity-related changes.
then looked at different cell types and molecules inside and around the tumor, collectively known as tumor micro-environments.
found that tumors in mice on a high-fat diet grew faster than mice on a normal diet.
only occur in immunogenic cancers, which may contain large numbers of immune cells, are more easily identified by the immune system, and are more likely to trigger an immune response.
, the study revealed that differences in tumor growth associated with diet are particularly dependent on the activity of CD8-T cells, immune cells that target and kill cancer cells.
if the CD8-T cells in the mice were removed, diet had no effect on tumor growth.
, the high-fat diet reduced the presence of CD8-T cells in tumor micro-environments, but did not reduce the presence of CD8-T cells elsewhere in the body.
, CD8-plus T cells left in tumors in mice on a high-fat diet became weaker: they split more slowly and became less active.
but when these cells are isolated and grow in the lab, they have normal activity, suggesting that something in the tumor impairs the function of these cells.
researchers also found that in obese mice, key free fatty acids (the main fuel source for cells) in the tumor micro-environment were depleted, even though the rest of the body was rich in fat.
led them to further analyze the metabolic characteristics of different cell types in tumors under normal and high-fat diets.
analysis showed that cancer cells respond to changes in fat content.
in a high-fat diet, cancer cells are able to reprogram their metabolism to increase fat intake and utilization, while CD8-T cells do not.
eventually depletes some fatty acids in the tumor's micro-environment, making T cells lack the necessary fuel.
through several different approaches, including single-cell gene expression analysis, large-scale protein surveys, and high-resolution imaging, the team identified a variety of dietary-related changes in the metabolic pathways of cancer cells and immune cells in tumor micro-environments.
particularly interesting is PHD3, a protein that has been shown in normal cells to inhibit excessive fat metabolism.
, the expression of PHD3 in cancer cells in obese environments decreased significantly compared to normal environments.
when researchers forced tumor cells to overexploit PHD3, they found that it reduced the ability of tumors in obese mice to absorb fat while restoring the availability of key free fatty acids in tumor micro-environments.
expression of PHD3 significantly reversed the negative effects of a high-fat diet on immune cell function in tumors.
tumors with high expression of PHD3 grew more slowly in obese mice than tumors that had low expression of PHD3.
this is a direct result of the increased activity of CD8-T cells.
in obese mice lacking CD8-T cells, differences in PHD3 expression did not affect tumor growth.
team also analyzed the human tumor database and found that low expression of PHD3 was associated with immunologically "cold" tumors with fewer immune cells.
researchers believe this link suggests that tumor fat metabolism plays an important role in human diseases and that obesity reduces the immune response to anti-tumors in many cancers.
, the scientists believe the results provide a basis for a better understanding of how obesity affects cancer and how metabolism affects outcomes.
it's too early to say whether PHD3 is the best therapeutic target, the findings open the door to new strategies to fight cancer through metabolic weaknesses.
" cancer immunotherapy has had a huge impact on a patient's life, but not everyone can benefit from it.
now, we know that the tug-of-war between T-cells and tumor cells will change due to obesity, which will help us think about and develop new immunotherapy and combination therapies.
" said Arlene Sharpe, a professor of comparative pathology who co-led the study.
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