Nanoparticles to Restore Efficiency in Exhausted Cancer-Killing Cells

Natural killer cells are lymphocytes in the human immune system that fight cancer and viral infections but often lose their functionality in the tumor micrenvironment. A promising study by Professor Mira Barda-Saad and her team from the Faculty of Life Sciences at Bar-Ilan University has discovered what exhausts these killer cells and how to restore them to effective activity in the fight against tumors.

In recent years, the landscape of cancer treatment has been transformed by the rise of immunotherapeutic strategies, such as the Chimeric Antigen Receptor (CAR) approach. This method involves extracting patient cells, modifying them genetically in a laboratory to enhance their ability to combat cancer cells, and then reintroducing them into the body. However, it has been recently discovered that these "engineered" natural killer (NK) cells can become fatigued from continuously battling tumors. Professor Barda-Saad's research team has identified the underlying causes of NK cell exhaustion and developed a novel solution using nanoparticles to restore the vitality of these cells directly within the patient, eliminating the need to isolate from the patient.

Natural killer cells play a crucial role in the immune system, as they can identify disease-causing agents without prior sensitization and contribute to the control of viral infections and cancer cells. However, a significant portion of these cells, about 13%, do not receive balanced molecular signals during their training and become 'non-functional' cells that do not act against cancer cells or viruses.

The molecular events leading to the dysfunction of natural killer cells, including exhaustion resulting from unbalanced overstimulation, occur during their training in the immune system or in the tumor environment. These exhaustion processes have not been thoroughly characterized until now.

Thorough Research: Professor Barda-Saad's group meticulously characterized the phenotype (genetic expression) of the exhausted cells and demonstrated functional, transcriptional, and phenotypic similarity between killer cells exhausted in their training process and killer cells exhausted in the tumor microenvironment. In both states, the cells are non-functional. Additionally, Barda-Saad's research group identified two negative regulatory factors: an enzyme called DGK alpha and the genetic transcription factor Egr2, which are responsible for the non-functional state and whose expression increases in it.

Hope for the Future: experiments in three-dimensional tissue culture have shown that nanoparticles, acting as a platform for drug delivery, can reprogram the exhausted killer cell population. After the research group introduced nanoparticles that silence the two negative regulators, the killer cells returned to their normal function and efficiently killed cancer cells. These promising findings, obtained in model animals bearing aggressive pancreatic cancer, could pave the way for the development of effective treatments against tumors using an immunotherapeutic strategy.

Given the novelty of the findings, the research was published in the scientific journal The EMBO Journal in the field of molecular biology and served as the cover. To read the article: https://www.embopress.org/doi/full/10.1038/s44318-024-00094-5