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Memory-like natural killer cell and CD19-antibody based immunotherapy in combination with tyrosine-kinase inhibition of Ph(-like) acute lymphoblastic leukemia (RNA-Seq)

ABSTRACT: Epigenetic reprogramming determines transcriptional output of preactivated NK cells. We conducted RNA-sequencing on individually sorted NKC cells to analyze the transcriptional pattern of preactivated and canonical NK cells when exposed to K562 target cells.Gene set enrichment analysis (GSEA) of DEG analysis results showed a positive enrichment of the following Gene Ontology (GO) terms among others: Ribosome and mitochondrial function, immune system process, cell adhesion and motility. In general, the pre-activation of bead-isolated NK cells induced by IL12/15/18 and mbIL-21/4-1BB K562 expansion results in significant epigenetic reprogramming and enhanced transcriptional output. The epigenetic and transcriptional characteristics of IL12/15/18 pre-activated bead-isolated NK cells closely resemble those of mbIL-21/4-1BB K562 cell co-culture expanded NK cells, suggesting that a memory-like state can be induced in NK cells solely through IL21 4-1BB K562 co-culture conditions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE268063 | GEO | 2025/03/14

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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Memory-like natural killer cell and CD19-antibody based immunotherapy in combination with tyrosine-kinase inhibition of Ph(-like) acute lymphoblastic leukemia (RNA-Seq)

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