Nanoparticles can revive exhausted cancer-fighting immune cells

In the fight against cancer, not only are the body and mind exhausted, but our body's natural killer cells (NK cells) – a central component of our immune system – also become tired and lose their function if they have to continue fighting the disease.

A new study from Bar-Ilan University now offers a novel method for regenerating NK cells using nanoparticles, restoring their vitality and giving them the strength to continue fighting cancer cells.

Cancer is the second leading cause of death in the United States after heart disease. The American Cancer Society estimates that there will be two million new cases of cancer in the country by 2024—about 5,480 new diagnoses per day.

NK cells are an important component of the immune system and are crucial for identifying and destroying cancer and virus cells.

In recent years, doctors have begun working with immunotherapeutic strategies such as the chimeric antigen receptor (CAR) approach to extract patient cells, genetically modify them in the laboratory to improve their ability to fight cancer cells, and then reintroduce them into the body.

However, recent research has shown that lymphocytes – either T cells or NK cells, including genetically modified NK cells – can become fatigued by the continuous fight against tumors and subsequently lose their function.

To circumvent this process, Prof. Mira Barda-Saad and a team of researchers from the Goodman Faculty of Life Sciences identified the underlying causes of NK cell dysfunction and developed a novel solution.

They use nanoparticles that specifically target and silence negative regulators and restore NK cell activity directly in the patient's body, bypassing the need for cell extraction and genetic modification.

Revitalization of natural killer cells

According to the researchers, NK cell dysfunction occurs in two ways. The first is during the immune system's “training process.” If this process is disrupted and the NK cells receive inappropriate signals, it can result in “anergenic” NK cells that do not function properly.

The second factor is the tumor microenvironment. When NK cells encounter a tumor, they are constantly stimulated. If this stimulation is excessive and prolonged, it can lead to exhaustion, making the NK cells less effective at fighting the cancer.

Barda-Saad's group analyzed anergic and exhausted NK cells from both their training phase and the tumor microenvironment and found that they are similarly dysfunctional. They identified two key factors contributing to this dysfunction: the enzyme DGK alpha and the transcription factor Egr2.

“Experiments in three-dimensional tissue culture and in vivo mice have shown that nanoparticles serving as a platform for drug delivery can reprogram the dysfunctional natural killer cell population,” said Barda-Saad.

“After the research group introduced nanoparticles that silenced the two negative regulators, the killer cells resumed their normal function and efficiently killed cancer cells.”

These promising findings, obtained in animal models of aggressive pancreatic cancer, may pave the way for the development of effective treatments against solid tumors using an immunotherapeutic strategy and provide hope to patients and professionals in the field.

The study recently appeared on the cover of The EMBO Journal.