Reprogramming a more potent cytotoxic Human iPSC-Derived NK Cells


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. As such, they hold great promise as the basis for anticancer therapies, able to identify and target malignant cells, but their efficacy has proven limited.

To advance the potential held by NK cells, A team of scientists led by Professor Dan Kaufman at the division of regenerative medicine and director of cell therapy at UCSD School of Medicine reprogrammed skin or blood cells to become iPSCs, which were then directed to become NK cells. This strategy produces a standardized cell population, rather than needing to isolate cells on a patient-specific basis. The research work is now published in journal Cell Stem Cell. The cells lack a gene called CISH, which encodes cytokine-inducible SH2-containing protein, a checkpoint or braking mechanism that is ordinarily expressed by NK cells that are stimulated by cytokines such as interleukin-15 (IL-15). Without this braking mechanism, NK cells can go on a killing spree.

According to experimental evidence, the human iPSC-derived NK cells have greater cytotoxic activity in vitro. They are also better at inhibiting tumor progression in vivo. Finally, they display greater metabolic fitness—just the thing to keep a killing spree going.

The authors 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. Their studies demonstrate that it is possible to edit iPSC-derived NK cells to remove an inhibitory gene inside the cell to improve activation of NK cells.

The researchers also demonstrated that the CISH deletion improves NK cell function in at least two different ways. First, it removes a brake on IL-15 signaling, which improves NK cell activation and function, even at low IL-15 concentrations. Second, it leads to metabolic reprogramming of the NK cells. They become more efficient at energy utilization, which improves their function in vivo.

Next, the researchers deleted the CISH gene in the iPSC-derived NK cells. Lacking this gene, the iPSC-derived NK cells demonstrated increased IL-15-mediated JAK-STAT signaling, a mechanism that alerts immune system cells, such as macrophages, lymphocytes, and fibroblasts to sites of infection, inflammation, and trauma. They also showed that CISH−/− iPSC-NK cells exhibit improved expansion and increased cytotoxic activity against multiple tumor cell lines when maintained at low cytokine concentrations. “CISH−/− iPSC-NK cells display significantly increased in vivo persistence and inhibition of tumor progression in a leukemia xenograft model.

Mechanistically, CISH−/− iPSC-NK cells displayed improved metabolic fitness characterized by increased basal glycolysis, glycolytic capacity, maximal mitochondrial respiration, ATP-linked respiration, and spare respiration capacity mediated by mammalian target of rapamycin (mTOR) signaling that directly contributes to enhanced NK cell function.

The research team plans to translate their findings into a clinical therapy with their CISH-deleted iPSC-NK cells to provide an even more effective treatment.

Reprogramming a more potent cytotoxic Human iPSC-Derived NK Cells - Medicine Innovates



Huang Zhu, Robert H.Blum, Davide Bernareggi, Eivind Heggernes Ask, Zhengming Wu, Hanna Julie Hoel, Zhipeng Meng, Cheng sheng Wu, Kun-Liang Guan, Karl-Johan Malmberg, Dan S.Kaufman. Metabolic Reprograming via Deletion of CISH in Human iPSC-Derived NK Cells Promotes In Vivo Persistence and Enhances Anti-tumor Activity. Cell Stem Cell, Available online 11 June 2020

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