December 5, 2023

An essential nutrient in cells is key to maintaining the body’s immune response against cancer, new research has found. The discovery could lead to more effective treatments for the disease.

The adaptive immune system, also known as acquired immunity, uses specific antigens to mount a strategic immune response. Unlike the innate immune system, which attacks based on recognizing general threats, adaptive immunity is activated by exposure to invaders such as cancer and uses immune memory to learn about threats and respond accordingly.

Some cancer cells are able to evade the body’s adaptive immune response, especially cancer-killing T cells, although the mechanisms for this process are poorly understood. Dendritic cells (DCs) are a unique cellular system known to “prime” T cells, priming them to fight cancer.

New research from St. Jude Children’s Research Hospital takes a closer look at how cancer cells and dendritic cells interact and finds that a fundamental energy-producing nutrient plays a key role in maintaining the immune system’s ability to destroy tumors.

The nutrient in question is glutamine. Glutamine performs several functions in the body, but one of the more important functions is to provide fuel for immune cells. These cells and rapidly dividing cells such as cancer cells consume it in large quantities.

The researchers found that in the tumor microenvironment, immune cells and cancer cells compete for glutamine. If it’s monopolized by cancer cells, there’s less glutamine left for dendritic cells, meaning they may not have the energy to muster the T cells needed to attack the tumor.

“It’s a nutritional tug-of-war between tumor cells and immune cells,” said Hongbo Chi, corresponding author of the study. “If tumor cells use all the glutamine available, a specialized immune cell type called dendritic cells becomes glutamine deficient, leading to impaired antitumor immunity. But if we can replenish the tumor microenvironment with Sufficient glutamine, this will inhibit tumor growth as dendritic cells use it and activate the adaptive immune response.”

The researchers found that supplementing glutamine in the tumor microenvironment improved the ability of DCs to activate T cells and severely reduced tumor growth. This study is the first to identify a nutrient as a major signal between cancer cells and DCs in the tumor microenvironment.

“Although T cells are the cornerstone of cancer-fighting immunity, they cannot do this job alone,” Chi said. “We can think of dendritic cells as drivers and T cells as cars. Doesn’t move. Plus, nutrients like glutamine serve as a driver’s license.”

The researchers say their findings could improve current cancer treatments.

“We are very excited to be able to establish a link between glutamine, treatment effects and dendritic cells,” said Chuansheng Guo, lead author of the study. “This is critical for the efficacy of immune checkpoint blockade and adoptive cell transfer therapies.”

The immune system distinguishes normal cells from cancer cells by using “checkpoint” proteins on immune cells. A checkpoint is like a switch that needs to be turned on to initiate an immune response. Cancer cells can use checkpoints to send deceptive signals telling T cells that they are harmless, and immune checkpoint blockers prevent cancer cells from doing so. In adoptive cell transplantation, T cells from patients or other individuals are given to patients to help their bodies fight diseases such as cancer.

The study also found that two proteins, FLCN and SLC38A2, respond to, or take up, glutamine in dendritic cells, and when removed, the antitumor effects of glutamine supplementation were lost. These proteins could be potential drug targets, the researchers say.

“This paper provides a proof of concept that nutrients can work synergistically with checkpoint inhibitors as a new combination therapy strategy to treat tumors,” Chi said.

The study was published in the journal nature.

source: St. Jude Children’s Research Hospital