Tumor- and cytokine-primed human natural killer cells exhibit distinct phenotypic and transcriptional signatures

Sabry, M., Zubiak, A., Hood, S.P., Simmonds, P., Arellano-Ballestero, H., Cournoyer, E., Mashar, M., Pockley, A.G. ORCID: 0000-0001-9593-6431 and Lowdell, M.W., 2019. Tumor- and cytokine-primed human natural killer cells exhibit distinct phenotypic and transcriptional signatures. PLoS ONE, 14 (6): e0218674. ISSN 1932-6203

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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.

Item Type: Journal article
Publication Title: PLoS ONE
Creators: Sabry, M., Zubiak, A., Hood, S.P., Simmonds, P., Arellano-Ballestero, H., Cournoyer, E., Mashar, M., Pockley, A.G. and Lowdell, M.W.
Publisher: Public Library of Science
Date: 2019
Volume: 14
Number: 6
ISSN: 1932-6203
Identifiers:
NumberType
10.1371/journal.pone.0218674DOI
Rights: Copyright: © 2019 Sabry et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Divisions: Schools > School of Science and Technology
Depositing User: Linda Sullivan
Date Added: 01 Jul 2019 11:31
Last Modified: 01 Jul 2019 11:31
URI: http://irep.ntu.ac.uk/id/eprint/36974

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