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.
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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15 July 2022
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, 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), .
(doi:10.4049/jimmunol.2101139).
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
Additional Information:
Funding Information:
This work was supported by a John Goldman Fellowship from Leukaemia UK to M.D.B. and grants from the Medical Research Council (519241101) and Cancer Research UK consortium “HUNTER” to S.I.K. The 10X Chromium Controller was funded by a Cancer Research UK Advanced Clinician Scientist Fellowship to Sean Hua Lim (A27179).
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© 2022 TheAuthors.
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Local EPrints ID: 468430
URI: http://eprints.soton.ac.uk/id/eprint/468430
ISSN: 0022-1767
PURE UUID: 206a9b5f-8852-4337-8a22-bbe1e3b68f5e
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Date deposited: 15 Aug 2022 16:40
Last modified: 17 Mar 2024 04:04
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Author:
Amber Doyle
Author:
Jack, Graham Fisher
Author:
Marta Ewa Polak
Author:
Lara, Victoria Graham
Author:
Andres Vallejo Pulido
Author:
Rebecca Fulton
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