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KIR2DS2 expression identifies NK cells with enhanced anticancer activity

KIR2DS2 expression identifies NK cells with enhanced anticancer activity
KIR2DS2 expression identifies NK cells with enhanced anticancer activity
NK cells are promising cellular therapeutics against hematological and solid malignancies. Immunogenetic studies have identified that various activating killer cell Ig-like receptors (KIRs) are associated with cancer outcomes. Specifically, KIR2DS2 has been associated with reduced incidence of relapse following transplant in hematological malignancies and improved outcomes in solid tumors, but the mechanism remains obscure. Therefore, we investigated how KIR2DS2 expression impacts NK cell function. Using a novel flow cytometry panel, we show that human NK cells with high KIR2DS2 expression have enhanced spontaneous activation against malignant B cell lines, liver cancer cell lines, and primary chronic lymphocytic leukemia cells. Surface expression of CD16 was increased on KIR2DS2high NK cells, and, accordingly, KIR2DS2high NK cells had increased activation against lymphoma cells coated with the clinically relevant anti-CD20 Abs rituximab and obinutuzumab. Bulk RNA sequencing revealed that KIR2DS2high NK cells have upregulation of NK-mediated cytotoxicity, translation, and FCGR gene pathways. We developed a novel single-cell RNA-sequencing technique to identify KIR2DS2+ NK cells, and this confirmed that KIR2DS2 is associated with enhanced NK cell–mediated cytotoxicity. This study provides evidence that KIR2DS2 marks a population of NK cells primed for anticancer activity and indicates that KIR2DS2 is an attractive target for NK-based therapeutic strategies.
0022-1767
379-390
Blunt, Matthew
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Cragg, Mark
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Doyle, Amber
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Fisher, Jack, Graham
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Khakoo, Salim
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Forconi, Francesco
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Johnson, Peter
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Polak, Marta Ewa
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Graham, Lara, Victoria
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Vallejo Pulido, Andres
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Fulton, Rebecca
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Carter, Matthew
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Blunt, Matthew
b1109de3-6045-4bc3-bd77-6cf26504697d
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c
Doyle, Amber
eff9eb33-8e3e-4597-9ef1-7b1015a5f343
Fisher, Jack, Graham
5d9176a9-c6a6-4234-a178-3054eee07eb4
Khakoo, Salim
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Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Johnson, Peter
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Polak, Marta Ewa
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Graham, Lara, Victoria
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Vallejo Pulido, Andres
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Fulton, Rebecca
848aa9dc-797f-40f8-b63d-bca0d90f7b55
Carter, Matthew
3baac102-d80c-42ba-ab4d-ad339a48169e

Blunt, Matthew, Cragg, Mark, Doyle, Amber, Fisher, Jack, Graham, Khakoo, Salim, Forconi, Francesco, Johnson, Peter, Polak, Marta Ewa, Graham, Lara, Victoria, Vallejo Pulido, Andres, Fulton, Rebecca and Carter, Matthew (2022) KIR2DS2 expression identifies NK cells with enhanced anticancer activity. The Journal of Immunology, 209 (2) (2), 379-390. (doi:10.4049/jimmunol.2101139).

Record type: Article

Abstract

NK cells are promising cellular therapeutics against hematological and solid malignancies. Immunogenetic studies have identified that various activating killer cell Ig-like receptors (KIRs) are associated with cancer outcomes. Specifically, KIR2DS2 has been associated with reduced incidence of relapse following transplant in hematological malignancies and improved outcomes in solid tumors, but the mechanism remains obscure. Therefore, we investigated how KIR2DS2 expression impacts NK cell function. Using a novel flow cytometry panel, we show that human NK cells with high KIR2DS2 expression have enhanced spontaneous activation against malignant B cell lines, liver cancer cell lines, and primary chronic lymphocytic leukemia cells. Surface expression of CD16 was increased on KIR2DS2high NK cells, and, accordingly, KIR2DS2high NK cells had increased activation against lymphoma cells coated with the clinically relevant anti-CD20 Abs rituximab and obinutuzumab. Bulk RNA sequencing revealed that KIR2DS2high NK cells have upregulation of NK-mediated cytotoxicity, translation, and FCGR gene pathways. We developed a novel single-cell RNA-sequencing technique to identify KIR2DS2+ NK cells, and this confirmed that KIR2DS2 is associated with enhanced NK cell–mediated cytotoxicity. This study provides evidence that KIR2DS2 marks a population of NK cells primed for anticancer activity and indicates that KIR2DS2 is an attractive target for NK-based therapeutic strategies.

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Accepted/In Press date: 8 May 2022
Published date: 15 July 2022

Identifiers

Local EPrints ID: 468430
URI: http://eprints.soton.ac.uk/id/eprint/468430
ISSN: 0022-1767
PURE UUID: 206a9b5f-8852-4337-8a22-bbe1e3b68f5e
ORCID for Matthew Blunt: ORCID iD orcid.org/0000-0003-1099-3985
ORCID for Mark Cragg: ORCID iD orcid.org/0000-0003-2077-089X
ORCID for Jack, Graham Fisher: ORCID iD orcid.org/0000-0002-5090-7503
ORCID for Francesco Forconi: ORCID iD orcid.org/0000-0002-2211-1831
ORCID for Peter Johnson: ORCID iD orcid.org/0000-0003-2306-4974
ORCID for Andres Vallejo Pulido: ORCID iD orcid.org/0000-0002-4688-0598

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Date deposited: 15 Aug 2022 16:40
Last modified: 24 Nov 2022 02:44

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Contributors

Author: Matthew Blunt ORCID iD
Author: Mark Cragg ORCID iD
Author: Amber Doyle
Author: Jack, Graham Fisher ORCID iD
Author: Salim Khakoo
Author: Peter Johnson ORCID iD
Author: Marta Ewa Polak
Author: Lara, Victoria Graham
Author: Andres Vallejo Pulido ORCID iD
Author: Rebecca Fulton
Author: Matthew Carter

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