In a recent study published in the international journal Cell Stem Cell, scientists from the University of California and other institutions have developed natural killer cells with enhanced activity against specific leukemias in vivo and in vitro by using induced pluripotent stem cells (ipsCs) and eliminating a key gene; natural killer cells (NK cells) are a key component of the body’s innate immune system, along with T cells and B cells. Natural killer cells (NK cells) are lymphocytes that belong to the same family as T and B cells and are a key component of the body’s innate immune system, capable of circulating in the body and acting as the body’s first line of immune defense against foreign invaders, mainly a wide range of pathogens and cancers, among others.
NK cells are also expected to help researchers develop novel anti-cancer therapies because of their ability to identify and target malignant cells, but their efficiency of action is very limited; in this study, the researchers used two approaches to improve the action potential of NK cells. First, they used ipsCs derived from skin or blood cells to develop NK cells that can be reprogrammed to return to an embryonic-like multipotential state and transformed directly into NK cells, a strategy that generates a standardized population of cells rather than isolating cells on a patient-by-patient basis.
Second, the researchers eliminated a gene in stem cell-derived NK cells called CISH, which regulates the expression of specific proteins that inhibit cytokine signaling, a class of specialized molecules that send signals like other immune system cells, including macrophages, lymphocytes and fibroblasts, allowing these cells to reach sites of infection, inflammation and trauma. These immune cells include macrophages, lymphocytes and fibroblasts, which enable these cells to reach sites of infection, inflammation and trauma. When NK cells are stimulated by cytokines such as IL15, CISH elimination from NK cells may remove internal checkpoints that are normally activated or expressed, and CISH-killed ipsC-derived NK cells are effective in treating mice carrying human leukemia cells, while mice treated with unmodified NK cells die of leukemia, said researcher Kaufman .
The findings suggest that researchers were able to edit ipsC-derived NK cells to remove inhibitory genes within the cells, thereby improving NK cell activation. CISH knockout improves NK cell function in at least two different ways: first, it removes the braking effect on IL15 signaling and improves NK cell activation and function, even at lower IL15 concentrations, and second, it reprograms NK cells metabolically to make them more efficient at energy utilization, thereby improving cell function in vivo.
The researchers are currently in the process of translating the results of this paper into clinical therapies, and as iPSC-derived NK cells are used in clinical trials to treat hematologic tumors and solid tumors, the researchers expect that iPSC-NK cells that exclude CISH may be able to serve as a more effective treatment. Finally, the researchers say that it is important that iPSCs provide a stable platform for genetic modification and that NK cells can also be used as allogeneic cells so that individual patients do not need to be matched, allowing researchers to create a series of modified ipsC-derived NK cells that can be used as a standardized therapy to treat hundreds or thousands of patients.