Tumor- and cytokine-primed human natural killer cells exhibit distinct phenotypic and transcriptional signatures.
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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2019-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0218674 |
| _version_ | 1819108741580062720 |
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| author | May Sabry Agnieszka Zubiak Simon P Hood Poppy Simmonds Helena Arellano-Ballestero Eily Cournoyer Meghavi Mashar A Graham Pockley Mark W Lowdell |
| author_facet | May Sabry Agnieszka Zubiak Simon P Hood Poppy Simmonds Helena Arellano-Ballestero Eily Cournoyer Meghavi Mashar A Graham Pockley Mark W Lowdell |
| author_sort | May Sabry |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T03:14:45Z |
| format | Article |
| id | doaj.art-9a94e098d2fb4a44a28230a6efbf53a6 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-22T03:14:45Z |
| publishDate | 2019-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-9a94e098d2fb4a44a28230a6efbf53a62022-12-21T18:40:51ZengPublic Library of Science (PLoS)PLoS ONE1932-62032019-01-01146e021867410.1371/journal.pone.0218674Tumor- and cytokine-primed human natural killer cells exhibit distinct phenotypic and transcriptional signatures.May SabryAgnieszka ZubiakSimon P HoodPoppy SimmondsHelena Arellano-BallesteroEily CournoyerMeghavi MasharA Graham PockleyMark W LowdellAn 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.https://doi.org/10.1371/journal.pone.0218674 |
| spellingShingle | May Sabry Agnieszka Zubiak Simon P Hood Poppy Simmonds Helena Arellano-Ballestero Eily Cournoyer Meghavi Mashar A Graham Pockley Mark W Lowdell Tumor- and cytokine-primed human natural killer cells exhibit distinct phenotypic and transcriptional signatures. PLoS ONE |
| title | Tumor- and cytokine-primed human natural killer cells exhibit distinct phenotypic and transcriptional signatures. |
| title_full | Tumor- and cytokine-primed human natural killer cells exhibit distinct phenotypic and transcriptional signatures. |
| title_fullStr | Tumor- and cytokine-primed human natural killer cells exhibit distinct phenotypic and transcriptional signatures. |
| title_full_unstemmed | Tumor- and cytokine-primed human natural killer cells exhibit distinct phenotypic and transcriptional signatures. |
| title_short | Tumor- and cytokine-primed human natural killer cells exhibit distinct phenotypic and transcriptional signatures. |
| title_sort | tumor and cytokine primed human natural killer cells exhibit distinct phenotypic and transcriptional signatures |
| url | https://doi.org/10.1371/journal.pone.0218674 |
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