Directly reprogram natural killer cells to obtain stronger treatment effects

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Nature Sub-Journal: Directly reprogram natural killer cells to obtain stronger treatment effects

Directly reprogram natural killer cells to obtain stronger treatment effects.  In the long course of human evolution, we have always faced many invisible killers. Among them, there are not only foreign enemies such as bacteria and viruses, but also the “traitors” in the body that are out of control due to genetic mutations-cancer cells. Fortunately, in this struggle throughout the evolutionary history, humans have also evolved a powerful weapon-the immune system.

With the development of biology and medicine, humans’ understanding of cancer and their own immune system has gradually deepened, and tumor immunotherapy is in the ascendant. As the name suggests, immunotherapy is to activate the immune system of cancer patients and make it clear the tumor tissue on its own, which brings new hope to the majority of cancer patients.

It is worth noting that the source of effective and available natural killer (NK) cells will expand their use as immunotherapeutics, especially for solid cancers.

Recently, researchers from the Korea Institute of Bioscience and Biotechnology  (KRIBB) published a research paper titled: Directly reprogrammed natural killer cells for cancer immunotherapy in the sub-Journal Nature Biomedical Engineering.

The research team proved that using pluripotent transcription factors and optimized reprogramming medium, human somatic cells can be directly reprogrammed into natural killer (NK) cells with a CD56+CD16+ phenotype. Directly reprogrammed NK cells have strong innate adaptive immunomodulatory activity and strong killing ability to a variety of cancer cells, including solid cancers and cancer stem cells that are difficult to treat.

Natural Killer Cells (NK) are important immune cells in the body, which are related to anti-tumor, anti-viral infection and immune regulation. Previous studies have found that the use of NK cells for immunotherapy can overcome the limitations of T cell anti-cancer immunotherapy and play an important role in cancer research and treatment.

It is worth noting that, compared with T cells, the recognition of target cells by NK cells is antigen-nonspecific and is not restricted by the major histocompatibility complex (MHC). Not only that, NK cells can also selectively kill quiescent or non-proliferating cancer stem cells related to cancer drug resistance, recurrence and metastasis.

Therefore, NK cells are considered to be a promising and long-lasting cancer treatment strategy.

In this study, the research team tried to obtain NK cells through direct reprogramming mediated by pluripotent transcription factors (Oct4, Sox2, Klf4, c-Myc). The researchers focused on optimizing the NK fate-specific reprogramming medium, and they found that using a combination of Wnt signaling activator and aryl hydrocarbon receptor (AhR) inhibitor is the most effective in the production of direct reprogramming of NK cells (drNK).

Research results show that peripheral blood mononuclear cells (PBMC) and T cells have high availability and ease of use, and are ideal starting cell choices for the production of drNK cells

The generation of drNK cells

The researchers also used flow cytometry to detect the phenotypic characteristics of drNK cells. They found that most drNK cells were double positive for CD56 and CD16, while other lineage markers such as CD19 (B cells) and CD14 (monocytes) were positive. Negative. In addition, comparing transcription and immunophenotypes showed that although drNK cells and traditional NK cells have some differences, the main phenotypes are still relatively similar.

Most drNK cells are double positive for CD56 and CD16

Next, the research team evaluated their anti-tumor ability by measuring the ability of drNK cells to induce cytolytic activity, cytokine secretion and degranulation. It is worth noting that even in the absence of stimulation, drNK cells can extensively kill various blood cancer cells and solid cancer cells, which proves that drNK cells have a strong ability to kill various cancer cells.

Not only that, the research team evaluated the anti-cancer stem cell (CSC) activity of drNK cells, for which the researchers constructed 3D cultures of colon cancer cells and corresponding mouse tumor models. Research results show that drNK cells can effectively target and kill a large number of colon cancer cells and cancer stem cells both in vivo and in vitro.

CSC killing activity of drNK cells

It is worth noting that CAR-T cell therapy is a new and very potential immunotherapy. Therefore, the research team constructed CAR-expressing drNK cells, that is, CAR-drNK cells, so that the toxicity and specificity of drNK cells can be redirected, thereby having specific and powerful anti-cancer activity against target cancer cells.

Construction of CAR-drNK cells

All in all, this graduate student has become directly reprogrammed NK cells-drNK cells, and confirmed in cell experiments, 3D tumor cultures and mouse tumor models: Compared with traditional NK cells, drNK cells are more effective in killing difficult to treat. Solid tumors and cancer stem cells, indicating that drNK cells have superior anti-cancer activity in the body.

The author wrote in the article: “Whether it is CAR-drNK cells or the combination of drNK cells and cytotoxic antibodies, they can produce selective and potent anti-cancer effects. The direct reprogramming of human somatic cells into NK cells is beneficial to The generation of autologous and allogeneic NK cells will help the design and testing of cancer immunotherapy and combination therapy!

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