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 have not been thoroughly characterized. We investigated the consequences of co-incubation with K562, CTV-1, Daudi RPMI-8226, and MCF-7 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 reveal the 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. Thus, it appears that tumor-mediated ligation of receptors on NK cells may induce a primed state which may or may not lead to full triggering of the lytic or cytokine secreting machinery. 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 encounters with tumor cells, independent of cytokine stimulation, and provide insight into tumor-specific NK cell responses to inform the transition toward harnessing the therapeutic potential of NK cells in cancer.
Highlights
Natural killer (NK) cell responses are influenced by signals from numerous germline-encoded receptors on the cell surface
Tumor-primed natural killer cell signature secretion, and tumor-specific gene expression signature induction in NK cells following priming with tumor targets, which is independent of cytokine stimulation
NK cells isolated from patients with cancer commonly display low levels of activation receptors, which has been associated with NK cell dysfunction [15, 27,28,29,30]
Summary
Natural killer (NK) cell responses are influenced by signals from numerous germline-encoded receptors on the cell surface. Pre-incubating NK cells with IL-2 results in the generation of a lymphokine-activated killer (LAK) cell, whereas pre-incubating with target tumor cells generates a “tumor-primed” NK cell (TpNK) [3, 4] In both cases, the “primed” state can be defined by an NK cell’s ability to kill target cells that previously exhibited little to no sensitivity to resting NK cells. The gamma-chain receptor associates with the Janus tyrosine-kinase (JAK)-3 to phosphorylate different downstream signal transducer and activator of transcription (STAT) molecules depending on the type of receptors engaged. Exposure to these cytokines alone or in combination with others, such as IL-12 or IL-18, can induce different and, in some cases synergistic, effects on NK cell effector functions. This cooperation can be achieved via non-redundant ligand combinations in target cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
