Immune system function is to detect and eliminate foreign pathogens, such as bacteria and viruses. Specific immune cells called T-cells do this by distinguishing between different types of proteins within cells, which allows them to detect the presence of infection or disease.

Similarly, another type of T-cells called cytotoxic T-cells recognize tumor cells by the specific mutated proteins called antigens they display on their surfaces and kill them. Unfortunately, many times, cancer cells grow unchecked despite the presence of T-cells.

Recent studies have shown that T-cells seem to become “exhausted”, no longer being able to eliminate cancer cells. The idea is that T-cells initially function well when they first face off against cancer cells, but gradually lose their ability to kill the cancer cells after repeated encounters. Researchers at the Vanderbilt School of Medicine have shown that T-cells become exhausted within hours after encountering cancer cells.

Perhaps this T-cell exhaustion explains why cancer immunotherapies such as immune checkpoint inhibitors and CAR-T cell therapy, which have shown remarkable promise by inducing remission in some patients, often fail to induce long-term responses in most patients.

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When and how do T-cells become exhausted?

By the time most patients are diagnosed with cancer, their immune system has been interacting with developing cancer cells for months to years. The Vanderbilt research team studied the differences between dysfunctional T-cells from tumors and highly functional T-cells from infected mice to identify the genes that code for critical proteins that T-cells use to regulate their function.

Initially, researchers analyzed different regulatory genes and pathways in T-cells encountering cancer cells compared to those of T-cells encountering infected cells. They reported that genes associated with inflammation were highly activated in T-cells interacting with infected cells but not in T-cells interacting with cancer cells.

They found that T-cells become dysfunctional with dramatically altered genetic structure within 5 days of encountering cancer cells in mice. In subsequent studies, they found multiple surprising hallmarks of T-cell dysfunction within 6 to 12 hours after they encountered cancer cells, including thousands of changes in genetic structure and gene expression.

Next, they found that very early DNA changes were stabilized and reinforced with continued exposure to cancer cells, effectively “imprinting” dysfunctional gene expression patterns in the T-cells. This meant that when the T-cells were removed from the tumors after five days and transferred to tumor-free mice, those T-cells remained dysfunctional.

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Stimulating T-cell killing function

Altogether, this research suggests that T-cells in tumors are not necessarily working hard and getting exhausted. Rather, T-cells are blocked right from the start by the negative signals sent out by the cancer cells into their surrounding environment, and alack of positive signals like inflammation results in a failure to get T-cells into high gear.

A new study led by Drs. Vardhana and Thompson at Sloan Kettering Institute has found that T-cell exhaustion starts with the cells’ metabolism — the chemical processes that enable cells to produce energy from nutrients. These changes in metabolism send T-cells down the path to exhaustion.

“We’ve shown that if you really want to rewire a T cell so it can be better at killing tumors, you have to change its metabolism,” Dr.Vardhana says.

At the same time, researchers from Vanderbilt are exploring strategies to stimulate the inflammatory pathways in T-cells encountering cancer cells, making those T-cells able to function as though they are encountering an infection and kill the cancer targets more effectively.

Consequently, it is important to optimize our metabolic functions (maintaining a constant low glucose/insulin response, reducing our baseline inflammation, normalizing hormones, etc.). At the same time, we should try to stimulate our immune function by supporting our Th1-cells, natural killer cells and cytotoxic T-cells through autophagy and specific dietary supplements.