New method uses nanoparticles to reprogram exhausted immune cells

A new study led by Professor Mira Barda-Saad and her research team at Bar-Ilan University’s Goodman School of Life Sciences has unveiled a novel method to rejuvenate natural killer (NK) cells in the fight against cancer. The study, published on the cover of The EMBO Journaladdresses a crucial challenge in cancer immunotherapy: NK cell exhaustion.

Natural killer cells, a key component of the immune system, are essential for identifying and destroying cancer cells and viruses. In recent years, the landscape of cancer treatment has been transformed by the rise of immunotherapeutic strategies, such as the CAR (Chimeric Antigen Receptor) approach. This method involves extracting cells from the patient, genetically modifying them in the laboratory to improve their ability to fight cancer cells, and then reintroducing them into the body.

Recently, however, it has been discovered that lymphocytes, whether T cells or NK cells, including “engineered” NK cells, can become exhausted from fighting tumors and lose their function. To circumvent this process, Professor Barda-Saad’s research team identified the underlying causes of NK cell dysfunction and developed a new solution using nanoparticles to restore the vitality of these cells directly within the patient.

These nanoparticles, capable of targeting and silencing negative regulators, restore NK cell activity directly in the patient’s body, bypassing the need for cell extraction and genetic modification.

NK cell dysfunction can occur in two ways:

1. During training, NK cells undergo a training process in the immune system. If this process is disrupted, it can lead to NK cell dysfunction.
2. In 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” where NK cells become less effective at fighting cancer. In essence, NK cell dysfunction can arise from inappropriate signals they receive during development (defined as “anergy”) or from the harsh conditions they face when fighting tumors (defined as “exhaustion”). Both NK cell populations – “anergic” and “exhausted” – are dysfunctional and these dysfunctional processes have not been fully characterized until now.

Professor Barda-Saad’s group analyzed anergic and exhausted NK cells both during their training phase and in the tumor microenvironment, and found that they exhibited similar dysfunctions. They identified two key factors contributing to this dysfunction: the enzyme DGK alpha and the transcription factor Egr2.

Experiments in three-dimensional tissue cultures and in vivo mouse models showed that nanoparticles, acting as a platform for drug delivery, can reprogram the dysfunctional population of natural killer cells. After the research group introduced nanoparticles that silenced the two negative regulators, the killer cells returned to their normal function and effectively killed the cancer cells.

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