Scientists Identify Pathway Driving Natural Killer Cell Activity

Medically reviewed by Laurie H. Glimcher, MD, and Rizwan Romee, MD

Immune cells called natural killer (NK) cells are a key arm of the body’s defenses against infections and cancers, but what provokes them into action is less well understood than some other immune components such as T cells. “Critical gaps in our knowledge regarding factors that play a key role in NK cell activation are an impediment to developing optimal NK cell-based immunotherapy treatments,” says Rizwan Romee, MD, a Dana-Farber physician-scientist who leads clinical trials involving NK cell therapy.

A new study by investigators at Dana-Farber Cancer Institute has identified a critical molecular pathway that drives NK cell responses against viral infections and cancer. This insight could aid scientists’ efforts to harness natural killer cells as a form of immunotherapy to treat tumors.

The research, reported in Nature Immunology, was led by Laurie H. Glimcher, MD, an immunologist and president and CEO of Dana-Farber. The scientists said there is “an urgent need for identifying new intrinsic regulators of NK cell-mediated immunity,” and their report appears to have found one.

This pathway has been extensively studied by Glimcher and colleagues. It has two components — the endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1 (IRE1 alpha) and a substrate transcription factor, X-box-binding protein 1 (XBP1). This signaling pathway is active in tumor cells and is known to be activated in immune dendritic cells, but it hasn’t been known whether the pathway drives NK cell function.

Making use of genetically engineered mouse models, Han Dong, PhD, a postdoctoral fellow with Glimcher, in collaboration with the laboratory of Joseph Sun, PhD, at Memorial Sloan Kettering Cancer Center, showed that the IRE1 alpha-XBP1 pathway is a positive regulator of NK cell proliferation and expansion in response to viral infection and also is engaged in NK cell-mediated protection against tumors.

When parts of the pathway were blocked, the scientists found that NK cells failed to expand in response to viral infection or melanoma tumors.

For all their promise, NK cells face potential drawbacks as cancer fighters in their inability to proliferate when infused into patients, and their short lifespan.

Romee commented, “The findings of this study are an important step towards our full understanding of the pathways critical for NK cell function and expansion.

“Future efforts,” he added, “will focus on potentially harnessing this pathway in two ways: to optimize NK cell expansion protocols used to generate large numbers of conventional and/or genetically modified NK cell numbers for clinical trials, and to improve their persistence and expansion after infusion into patients.”