Cancer cells protect themselves from immune cells by using a risky strategy—the release of potassium. It shuts down T cells by keeping them in an immature, stem-cell-like state. While the cancer cells blunt the T cells’ attack, they do so by enhancing T-cell properties that are useful in cancer immunotherapy. For example, the T cells retain the ability to replicate themselves. Consequently, they can fight another day, in greater numbers, after they have been removed from the potassium-rich tumor microenvironment and prepared for reintroduction to patients.

This possibility was uncovered by scientists based at the National Cancer Institute’s Center for Cancer Research (CCR). Working with mouse models of cancer, the scientists determined that tumor-induced immune suppression and the stem-cell-like properties of some antitumor T cells have something in common: the potassium released by dying cancer cells into the tumor microenvironment. The scientists also described how strategies to metabolically induce stemness programs in antitumor T cells could enhance tumor immunotherapies.

Details of this work appeared March 29 in the journal Science, in an article titled, “T cell stemness and dysfunction in tumors are triggered by a common mechanism.”

“We found that elevated extracellular potassium characteristic of the extracellular space within tumors reduced the uptake and consumption of local nutrients by antitumor T cells, inducing a state of functional caloric restriction,” the article’s authors indicated. “A starvation response ensued, resulting in autophagy, mitochondrially dominant metabolism, and a paucity of available cofactors obligatory for histone modification and the epigenetic remodeling required for progressive differentiation.”

Essentially, elevated potassium in the tumor microenvironment simultaneously suppressed T-cell function but also triggered stem-cell-like attributes in the cells, increasing their persistency, multipotency, and antitumor killing efficiency. In experiments with mice, the CCR scientists, led by Nicholas Restifo, MD, showed that T cells preconditioned with potassium outside the body displayed greater persistence and self-renewal upon reinfusion into tumor-bearing animals.

“Treatment of antitumor T cells with elevated extracellular potassium as well as pharmacologic or gene therapies mimicking mechanisms of functional starvation,” the article’s authors pointed out, “resulted in T cells with retained stemness, evidenced by self-renewal and multipotency, thereby enabling the enhanced destruction of large, established tumors.”

Restifo said that the next step will be clinical trials “to use this knowledge to make better treatments.” He is also excited about what the findings add to our current understanding of immunotherapy.

Some immunotherapy treatments, such as CAR T cells and immune checkpoint inhibitors, are limited by the life span of T cells. Cancer-fighting T cells inside the tumor can get “exhausted” and die. Therefore, researchers are exploring ways to help T cells used for immunotherapy not only last longer but replicate and grow.

“This study helps us better understand why cancer immunotherapy works the way it does,” noted Restifo. “It could also point the way toward generating better and more long-lasting responses to these treatments.”

“We’re harnessing the stemness capacity of T cells to treat cancer,” he emphasized. “For us, it’s huge. It explains how some immunotherapies work and suggests how we can improve them.”

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