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Human iPSC-derived NK cells armed with CCL19, CCR2B, high-affinity CD16, IL-15, and NKG2D complex enhance anti-solid tumor activity

ABSTRACT: Studies of chimeric antigen receptor (CAR)-T and -Natural killer (NK) cells have shown promising results in treating hematological malignancies. However, there are still obstacles to effectively treating solid tumors. These include the challenges of CAR-T cell homing and infiltration, the presence of immunosuppressive microenvironments, and the potential for antigen escape in solid tumors. To overcome the known limitations of immune cell therapy, we engineered human induced pluripotent stem cell (hiPSC)-derived NK (eNK) cells armed with CCL19, CCR2B, high-affinity CD16, IL-15, and NKG2D-DAP10 complex. We introduced the six genes into hiPSCs using the piggyBac system and stimulated them to differentiate into NK cells. Overexpression of NKG2D complex and high-affinity CD16 enhanced the antitumor function of the eNK cells. Overexpression of IL-15 prolonged the persistence of the eNK cells in vitro and in vivo. Forced expression of CCR2B enhanced eNK cell tumor infiltration. Forced expression of CCL19 endowed the eNK cells with the ability to recruit dendritic cells. We found that the eNK cells were able to lyse HLA-E-expressing tumor cells, but not normal human cells. These proof-of-concept studies demonstrate the promise of our eNK cells as a novel adoptive cell therapy product for the treatment of solid tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE247437 | GEO | 2025/06/10

REPOSITORIES: GEO

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Project description:Natural Killer cells (NK), a major constituent of innate immune system, have the ability to kill the transformed and infected cells without prior sensitization; can be put to immunotherapeutic use against various malignancies. NK cells discriminate between normal cells and transformed cells via a balance of inhibitory and activating signals induced by interactions between NK cell receptors and target cell ligands. Present study investigates whether expansion of NK cells could augment their anti-myeloma (MM) activity. For NK cell expansion, peripheral blood mononuclear cells from healthy donors and myeloma patients were co-cultured with irradiated K562 cells transfected with 4-1BBL and membrane-bound IL15 (K562-mb15-41BBL). A genome-wide profiling approach was performed to identify gene expression signature in expanded NK (ENK) cells and non-expanded NK cells isolated from healthy donors and myeloma patients. A specific set of genes involved in proliferation, migration, adhesion, cytotoxicity, and activation were up regulated post expansion, also confirmed by flow cytometry. Exp-NK cells killed both allogeneic and autologous primary MM cells more avidly than non-exp-NK cells in vitro. Multiple receptors, particularly NKG2D, natural cytotoxicity receptors, and DNAM-1 contributed to target lysis, via a perforin mediated mechanism. In summary, vigorous expansion and high anti-MM activity both in vitro and in vivo provide the rationale for testing exp-NK cells in a clinical trial for high risk MM. Differential gene expression profile in expanded natural killer (ENK) cells and non-expanded natural killer (NK) cells from healthy donors and myeloma patients Eight healthy donor and eight myeloma patients were used in the study. Non-expanded natural killer (NK) cells were isolated from PBMCs of healthy donors and myeloma patients. Expanded natural killer (ENK) cells were generated from same set of samples as mentioned in expansion protocol. All ENK and NK cells were used for gene expression profiling.

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Human iPSC-derived NK cells armed with CCL19, CCR2B, high-affinity CD16, IL-15, and NKG2D complex enhance anti-solid tumor activity

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