Researchers are gaining a better understanding about the impact of the tumor microenvironment on nutrient availability and the metabolic states of tumor cells and immune cells.

Susan M. Kaech, PhD, of Salk Institute for Biological Studies, chaired a symposium that explored the intersection of cancer metabolism and immunometabolism. The session, Metabolic and Nutritional Regulation of Cancer and Immunity, was originally presented Tuesday, April 12, and can be viewed on the virtual platform by registered meeting participants through July 13, 2022.

Matthew G. Vander Heiden, MD, PhD, of Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology and Dana-Farber Cancer Institute, discussed the influence of environmental factors on tumor growth.

Historically, cancer metabolism research has focused on genetic mutations, but there’s increasing evidence that three components determine how cancers carry out their metabolic programs: lineage, genetic mutations, and tissue environment.

“If you look at just primary tumor metabolic gene expression, it looks much more like the tissue where that cancer came from than it does like other cancers—the so-called lineage,” Vander Heiden said. “The way we have interpreted this data is that when a cell becomes cancer, it takes the existing metabolic program of that tissue, alters it in a way that’s different based on the genetic mutation, and this then creates a unique metabolic network that now can support the various things that tumor has to do.”

Taking into account the fact that cancers live within tissue environments where not all nutrients are available, Vander Heiden’s lab is exploring the hypothesis that limitations in tissue environments restrict how cells can use the networks they inherit from their lineage, and that this ultimately determines how different cancers function.

“Perhaps one of the barriers to metastasis is actually being able to access the right nutrient environment,” he said.

Mustapha Abubakar, MD, PhD, MSc, of the National Cancer Institute and a 2022 AACR NextGen Star, explained how the stromal microenvironment in nonmalignant breast tissue affects the risk of breast cancer development, drawing on data from a nested, case-control study of the Kaiser Permanente Northwest Benign Breast Disease Cohort. Using multivariable conditional logistic regression models that account for the histological classification of benign breast disease and established breast cancer risk factors, the investigators found a “striking” context-dependent correlation between stromal proportion and breast cancer risk, Abubakar said.

“Among patients with nonproliferativebenign breast disease, we found a strong association between increasing stromal proportion and reduced breast cancer risk. Among individuals with proliferative benign breast disease, we found the stroma to be associated with increasing breast cancer risk,” he explained. This may suggest that in the normal state, the stroma is protective against epithelial cell proliferation by maintaining epithelial cell polarity.

Lydia Lynch, PhD, of Harvard Medical School and Brigham and Women’s Hospital, discussed the relationship between dietary lipids and anti-tumor immunity.

“In obesity and in patients with cancer and in the tumor microenvironment, there’s systemic metabolic disruption. That changes the fuel that’s available to immune cells, which then changes their metabolism, changes their function, and then that can go back and change systemic metabolism,” she explained.

Thirteen cancers are associated with obesity, including esophageal cancer (35 percent), pancreatic cancer (28 percent), and kidney cancer (24 percent). And half of endometrial cancers are linked to excess body fat, Lynch said.

“There are many different molecules increased in obesity that can directly promote tumor growth, like different hormones, lipids, and insulin,” she added.

Tumors proliferate to a greater extent when given more lipids, as do Tregs (regulatory T cells) and gamma delta 17 T cells, but NK cells and CD8 T cells do not. This suggests targeted immunometabolic pathways may be beneficial in improving immunity in people with obesity and metabolic disorder, she explained.

In an effort to uncouple obesity from a high-fat diet, Lynch’s lab studied how mice responded to the same amount of fat in their diets from different sources, including animal sources such as lard and butter, and plant sources such as palm oil, peanut oil, and coconut oil.

“They’re becoming equally obese, but there are also no gross differences in their metabolism,” Lynch said of the mice. “But there still are very different impacts on their metabolome and on the immune cell metabolism, potentially leading to increased tumor growth.”

Kaech concluded the symposium with a presentation on co-opting tissue-resident macrophages to support cancer progression through metabolic reprogramming.

While some immune cells circulate, others have tissue residence, she explained. These tissue-resident macrophages are embryonically derived, infiltrating tissues as the tissues undergo patterning and developing specialized functions within the organs they inhabit.

Within the lung, alveolar macrophages play a key role in maintaining surfactant levels that are essential to keeping the airways healthy. Surfactant production is often greatly elevated in patients with lung cancer. Using mouse models, Kaech investigated whether changes within the environment cause the alveolar macrophages to transition into a more anti-inflammatory, tolerogenic state that promotes tumor progression.

The cytokine GM-CSF (granulocyte-macrophage colony-stimulating factor) drives alveolar macrophage proliferation and tumor progression, while alveolar macrophage peroxisome proliferator-activated receptor gamma (PPARγ) deletion delays tumor progression, Kaech explained. Her research further shows that the metabolic reprogramming that occurs in alveolar macrophages in response to changes in lipids within the environment is driven by PPARγ activity.

“These metabolic changes are now allowing, enhancing tumor growth, whereas deleting PPARγ, interfering with PPARγ and this metabolic reprogramming, shifts the cells from effluxing cholesterol and into storing cholesterol and other lipids, and this was associated with tumor suppression,” Kaech said.