Recent research indicates that a high-fat diet may weaken the immune system and hasten tumor growth. Prior studies have shown that obesity heightens the risk for more than 12 different types of cancer and is associated with poorer diagnoses and survival rates.
This research has also shed light on how obesity promotes tumor growth, with metabolic changes and chronic inflammation being key factors. A Harvard study released on December 9, 2020, discovered that obesity provides cancer cells with an advantage over immune cells in the battle for fuel.
Harvard Medical School researchers utilized mice to study the reaction of cancer cells to a high-fat diet. Published in the journal Cell, the study unveils new insights into the relationship between obesity and cancer, potentially influencing the future of immunotherapy.
The researchers observed that a high-fat diet diminishes the quantity and antitumor activity of CD8+T cells, a vital type of immune cell, within tumors. This occurs as cancer cells adapt their metabolism to take advantage of increased fat availability, thereby outcompeting T cells for fat molecules, leading to enhanced tumor growth.
Marcia Haigis, a professor of cell biology at the Blavatnik Institute at HMS and co-senior author of the study, noted, "Placing the same tumor in obese and nonobese environments shows that cancer cells adjust their metabolism in response to a high-fat diet." She added, "This discovery implies that a treatment effective in one scenario may not work as well in another, a consideration that is increasingly important in light of the obesity epidemic."
IMPLICATIONS FOR THIS RESEARCH ON THE FUTURE OF IMMUNOTHERAPY
The study indicated that inhibiting the metabolic reprogramming process reduced tumor growth in mice on high-fat diets. Presently, oncology nurses employ CD8+ T cells as the main method to enhance the immune response to cancer in immunotherapies. This new research could pave the way for improved immunotherapy approaches in the future.
"Cancer immunotherapies are significantly improving patients' lives, yet they don't work for everyone," stated co-senior author Arlene Sharpe, HMS George Fabyan Professor of Comparative Pathology and chair of the Department of Immunology at 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.”
In the study, researchers examined the impact of obesity on different types of cancer in mice, including breast, melanoma, and colorectal cancers. The mice were fed either a standard or a high-fat diet; those on the high-fat diet gained weight and showed other signs of obesity. Subsequently, the team investigated the various cell types and molecules within and surrounding the tumors, collectively referred to as the tumor microenvironment.
HOW CANCER CELLS REACTED TO HIGHER LEVELS OF FAT
The researchers found that tumors grew faster in mice on high-fat diets, but this was only true for immunogenic cancers, which are rich in immune cells and more easily recognized by the immune system, thus more likely to elicit a response.
The study indicated that the acceleration of tumor growth related to obesity was exclusively linked to the activity of CD8+ T cells, which are immune cells that attack and destroy cancer cells. If CD8+ T cells were removed, the diet had no effect on the rate of tumor growth. Notably, high-fat diets resulted in a reduction of these immune cells in the tumor microenvironment, but not elsewhere in the body.
WHAT THE TEAM DISCOVERED
The remaining cells in the tumor exhibited diminished vigor, dividing more sluggishly and showing signs of lethargy. Yet, when these cells were cultured in a laboratory setting, they displayed typical levels of activity. This suggested to the researchers that an element within the tumor environment was causing cellular dysfunction.
Moreover, the team discovered that in obese mice, the tumor microenvironment lacked significant free fatty acids, which are crucial for cellular fuel. In contrast, the rest of the body in these mice still maintained fatty acids, consistent with obesity.
Consequently, the researchers maintained a record of the metabolic profiles of tumor cells under high-fat and normal diets.
Their findings indicated that cancer cells adjust their metabolism in response to increased fat availability. With a high-fat diet, cancer cells modified their metabolic pathways to enhance fat uptake. In contrast, the immune cells did not undergo such reprogramming, resulting in a deficiency of essential fatty acids for these cells.
"The unexpected reduction in fatty acids was among the most startling discoveries of this research. It took us by surprise and propelled our subsequent analyses," stated Ringel, a postdoctoral researcher in the Haigis laboratory.
"The revelation that obesity and systemic metabolism can influence the fuel utilization by different cells within tumors was thrilling, and our metabolic atlas now enables us to dissect and comprehend these dynamics more thoroughly."
To investigate how different diets impacted cellular metabolism, the team employed single-cell gene expression profiling, extensive protein assessments, and high-resolution imaging. In their examination of the cells within the microenvironment, they focused on a protein known as PHD3.
This protein impedes fat absorption in typical cells. However, in the cancerous cells of obese mice, the levels of PHD3 were reduced compared to those in healthy mice.
When researchers increased PHD levels in cells, they noted a significant reduction in the tumor's fat consumption. This also resulted in the restoration of free fatty acids within the tumor microenvironment. Consequently, enhancing PHD3 expression mitigated the adverse effects of a high-fat diet on the function of immune cells. In obese mice, tumors exhibited slower growth rates when PHD3 levels were high compared to those with low PHD3.
This slowdown was attributed to heightened activity of immune cells; however, in obese mice lacking immune cells, PHD3 levels had no impact on tumor growth.
Although further research is necessary to ascertain PHD3's role in cancer treatment, this finding could shift scientific focus towards cellular metabolism.
"We aim to pinpoint pathways that could serve as targets to halt cancer progression and bolster immune anti-tumor response," stated Haigis. "Our research offers a detailed metabolic map for deriving insights into obesity, tumor immunity, and the interaction and rivalry between immune and tumor cells. It's probable that numerous other cell types and pathways remain to be discovered."
