When a foreign invader enters the body, natural killer (NK) cells of the immune system are mobilized and attack the invader, but they are not so effective at attacking and killing cancer cells. Researchers have been trying to harness NK cells for use in novel cancer treatments but report limited success; however researchers at the University of California San Diego have developed a technique for editing NK cells to improve their effectiveness at targeting cancer cells.
NK cells are lymphocytes that come from the same family as T and B cells and are part of the innate immune system. When there is a foreign invader, NK cells are amongst the first to go on the attack.
The researchers created NK cells from induced pluripotent stem cells (IPSCs) derived from skin and blood cells and eliminated the CISH gene. The CISH gene codes for a protein that inhibits cytokine signaling, which plays an important role in directing the NK cells to attack foreign invaders. The CISH gene is activated by cytokines such as IL-15.
The IPSC-NK cells were introduced in a mice with leukemia and the mice were cured, whereas mice that were not given the stem cells died from the cancer.
“Deletion of CISH in NK cells removes an internal ‘checkpoint’ that is normally activated or expressed when NK cells are stimulated by cytokines,” said Dan Kaufman, MD, PhD, professor of medicine in the Division of Regenerative Medicine, director of cell therapy at UC San Diego School of Medicine, and senior author of the study. Essentially, by removing CISH, the researchers took the foot off the brake on IL-15 signaling. That improved NK cell activation and function, even at low IL-15 concentrations. The researchers also report that without the CISH gene, the NK cells were more efficient at energy utilization, which improved their cancer-killing function in vivo.
T-cell therapies have shown tremendous promise and are now being used to treat some forms of blood cancer, but there is also considerable excitement about the use of NK cells in cancer therapy. In contrast to the T-cell therapies which involve harvesting cells from the patient, altering them and reintroducing them, NK treatments could be developed as an off-the-shelf treatment.
The researchers are now attempting to translate their research on IPSC-NK cells into a clinical therapy for leukemia. IPSC-derived NK cells are already being used in clinical trials to treat blood cancer and solid tumors. The researchers believe their IPSC-NK cells with CISH deleted could be used as a more effective treatment.
You can read more about the study in the paper – Metabolic Reprograming via Deletion of CISH in Human iPSC-Derived NK Cells Promotes In Vivo Persistence and Enhances Anti-tumor Activity – which was recently published in the journal Cell Stem Cell. DOI: 10.1016/j.stem.2020.05.008