The human natural killer (NK) cell line YTS as a novel platform for cellular therapy

The introduction of CAR T cells has revolutionized the treatment of lymphoma and myeloma. However, this approach has notable limitations, including severe adverse events, complex and costly production processes, dependence on the patient’s own T cells, and variability in the final product. In contrast, natural killer (NK) cells are not MHC-restricted, making them suitable for allogeneic use, and they do not trigger cytokine release syndrome. Despite these advantages, NK cell manufacturing remains complex and expensive.

YTS is a human NK cell line characterized by a limited number of activating receptors and can be easily cultured and transfected. In this study, we demonstrate that YTS cells transfected with a CD19-targeted CAR can serve as a novel immunotherapy against CD19-expressing cells. We show that CAR activity relies on intracellular signalling and, in certain tumors, on co-stimulation through the 2B4-CD28 pathway. Furthermore, we demonstrate that irradiation of engineered YTS cells prevents their proliferation while preserving their cytotoxic activity, even after freezing. Finally, we demonstrate that irradiated and frozen YTS cells expressing CAR CD19 significantly reduce CD19-expressing tumors in mice. We also generated YTS cells expressing the Fc receptor CD16 and showed they can mediate antibody-dependent cellular cytotoxicity (ADCC) against various tumors in vitro when treated with different antibodies.

We propose that genetically engineered YTS cells can serve as a novel, cost-effective, and accessible "off-the-shelf" immunotherapy, which can be tailored to target different antigens. These modified cells have potential applications in treating resistant lymphoma, autoimmune diseases, and solid tumors.