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Tumor- and cytokine-primed human natural killer cells exhibit distinct phenotypic and transcriptional signatures [RNA-seq]

ABSTRACT: An emerging cellular immunotherapy for cancer is based on the cytolytic activity of natural killer (NK) cells against a wide range of tumors. Although in vitro activation or ‘priming’ of NK cells by exposure to pro-inflammatory cytokines such as interleukin (IL)-2 has been extensively studied, the biological consequences of NK cell activation in response to target cell interactions are less characterized. Herein, we investigate the consequences of co-incubation with K562, CTV-1, Daudi and RPMI-8226 tumor cell lines on the phenotype, cytokine expression profile and transcriptome of human NK cells. We observe the downregulation of several activation receptors including CD16, CD62L, C-X-C chemokine receptor (CXCR)-4, natural killer group 2 member D (NKG2D), DNAX accessory molecule (DNAM)-1 and NKp46 following tumor-priming. Although this NK cell phenotype is typically associated with NK cell dysfunction in cancer, we show upregulation of NK cell activation markers such as CD69 and CD25, secretion of pro-inflammatory cytokines including macrophage inflammatory proteins (MIP-1) α /β and IL-1β/6/8 and overexpression of numerous genes associated with enhanced NK cell cytotoxicity and immunomodulatory functions such as FAS, TNFSF10, MAPK11, TNF and IFNG. Key signaling molecules exclusively affected by tumor-priming include MAP2K3, MARCKSL1, STAT5A, and TNFAIP3, which are specifically associated with NK cell cytotoxicity against tumor targets. Collectively, these findings help define the phenotypic and transcriptional signature of NK cells following their encounter with tumor cells, independent of cytokine stimulation, and provide insight into tumor-specific NK cell responses to inform the transition towards harnessing the therapeutic potential of NK cells in cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE130284 | GEO | 2019/06/12

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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Tumor- and cytokine-primed human natural killer cells exhibit distinct phenotypic and transcriptional signatures [RNA-seq]

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