Putting a type of immune cells in natural killer cells


Putting a type of immune cells in natural killer cells

Natural killer (NK) cells are lymphocytes in the same family as T and B cells, and are part of the innate immune system. They circulate throughout the body and are among the first to respond to the presence of foreign cells or invaders, most notably viruses and early signs of cancer.

First, they created NK cells from IPSCs, which are derived from skin or blood cells that have been reprogrammed back to an embryonic-like pluripotent state and then directed to become NK cells. This strategy produces a standardized cell population, rather than needing to isolate cells on a patient-specific basis

Second, the researchers deleted a gene called CISH in the stem cell-derived NK cells. The CISH gene regulates expression of a protein that suppresses cytokine signaling. Cytokines are molecules that signal other immune system cells, such as macrophages, lymphocytes and fibroblasts to sites of infection, inflammation and trauma.   

"Deletion of CISH in NK cells removes an internal 'checkpoint' that is normally activated or expressed when NK cells are stimulated by cytokines, such as IL15," said Kaufman. "We found that CISH-deleted iPSC-derived NK cells were able to effectively cure mice that harbor human leukemia cells, whereas mice treated with the unmodified NK cells died from the leukemia."

"These studies demonstrate that we can now edit iPSC-derived NK cells to remove an inhibitory gene inside the cell to improve activation of NK cells. We demonstrate that the CISH deletion improves NK cell function in at least two different ways. First, it removes a brake on IL15 signaling, with improves NK cell activation and function, even at low IL15 concentrations. Second, it leads to metabolic reprogramming of the NK cells. They become more efficient at energy utilization, which improves their function in vivo."

"As iPSC-derived NK cells are now in clinical trials to treat both hematologic (blood) malignancies and solid tumors, we expect that CISH-deleted iPSC-NK cells can provide an even more effective treatment.

"Importantly, iPSCs provide a stable platform for gene modification and since NK cells can be used as allogeneic cells that do not need to be matched to individual patients, we can create a line of appropriately modified iPSC-derived NK cells suitable for treating hundreds or thousands of patients as a standardized, 'off-the-shelf' therapy."

Immunogenetics: Open access journal focuses on the genetic research areas of autoimmune disorders such as multiple sclerosis, rheumatoid arthritis, Crohn’s disease, diabetes mellitus type 1, systemic lupus erythematous, etc. Articles on genetics of cell interaction with immune system, immune response to transplantation, immune based therapies for treatment of cancers, antigenic phylogeny of alleles, alloantigens are also welcome.

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Immunogenetics: open access