KIR2DS2+ NK cells in cancer patients demonstrate high activation in response to tumour-targeting antibodies
KIR2DS2+ NK cells in cancer patients demonstrate high activation in response to tumour-targeting antibodies
Strategies to mobilise natural killer (NK) cells against cancer include tumour-targeting antibodies, NK cell engagers (NKCEs) and the adoptive transfer of ex vivo expanded healthy donor-derived NK cells. Genetic and functional studies have revealed that expression of the activating killer immunoglobulin-like receptor KIR2DS2 is associated with enhanced function in NK cells from healthy donors and improved outcome in several different malignancies. The optimal strategy to leverage KIR2DS2+ NK cells therapeutically is however currently unclear. In this study, we therefore evaluated the response of KIR2DS2-expressing NK cells to activation against cancer with clinically relevant tumour-targeting antibodies and following ex vivo expansion. We identified that KIR2DS2high NK cells from patients with chronic lymphocytic leukaemia and hepatocellular carcinoma had enhanced activation in response to tumour-targeting antibodies compared to KIR2DS2- NK cells. However, the superior function of healthy donor derived KIR2DS2high NK cells was lost following ex vivo expansion which is required for adoptive transfer-based therapeutic strategies. These data provide evidence that targeting KIR2DS2 directly in cancer patients may allow for the utilisation of their enhanced effector function, however such activity may be lost following their ex vivo expansion.
Graham, Lara V.
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Fisher, Jack G.
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Doyle, Amber D.P.
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Sale, Ben
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Del Rio, Luis
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French, Albert J.E.
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Mayor, Neema P.
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Turner, Thomas R.
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Marsh, Steven G.E.
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Cragg, Mark S.
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Forconi, Francesco
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Khakoo, Salim
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Blunt, Matthew D.
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2 September 2024
Graham, Lara V.
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Fisher, Jack G.
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Doyle, Amber D.P.
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Sale, Ben
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Del Rio, Luis
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French, Albert J.E.
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Mayor, Neema P.
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Turner, Thomas R.
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Marsh, Steven G.E.
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Cragg, Mark S.
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Forconi, Francesco
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Khakoo, Salim
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Blunt, Matthew D.
b1109de3-6045-4bc3-bd77-6cf26504697d
Graham, Lara V., Fisher, Jack G., Doyle, Amber D.P., Sale, Ben, Del Rio, Luis, French, Albert J.E., Mayor, Neema P., Turner, Thomas R., Marsh, Steven G.E., Cragg, Mark S., Forconi, Francesco, Khakoo, Salim and Blunt, Matthew D.
(2024)
KIR2DS2+ NK cells in cancer patients demonstrate high activation in response to tumour-targeting antibodies.
Frontiers in Oncology, 14, [1404051].
(doi:10.3389/fonc.2024.1404051).
Abstract
Strategies to mobilise natural killer (NK) cells against cancer include tumour-targeting antibodies, NK cell engagers (NKCEs) and the adoptive transfer of ex vivo expanded healthy donor-derived NK cells. Genetic and functional studies have revealed that expression of the activating killer immunoglobulin-like receptor KIR2DS2 is associated with enhanced function in NK cells from healthy donors and improved outcome in several different malignancies. The optimal strategy to leverage KIR2DS2+ NK cells therapeutically is however currently unclear. In this study, we therefore evaluated the response of KIR2DS2-expressing NK cells to activation against cancer with clinically relevant tumour-targeting antibodies and following ex vivo expansion. We identified that KIR2DS2high NK cells from patients with chronic lymphocytic leukaemia and hepatocellular carcinoma had enhanced activation in response to tumour-targeting antibodies compared to KIR2DS2- NK cells. However, the superior function of healthy donor derived KIR2DS2high NK cells was lost following ex vivo expansion which is required for adoptive transfer-based therapeutic strategies. These data provide evidence that targeting KIR2DS2 directly in cancer patients may allow for the utilisation of their enhanced effector function, however such activity may be lost following their ex vivo expansion.
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fonc-1-1404051
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Accepted/In Press date: 13 August 2024
Published date: 2 September 2024
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Local EPrints ID: 500498
URI: http://eprints.soton.ac.uk/id/eprint/500498
ISSN: 2234-943X
PURE UUID: 6f52affa-a735-40bb-a295-0135983414dd
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Date deposited: 02 May 2025 16:31
Last modified: 22 Aug 2025 02:33
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Author:
Lara V. Graham
Author:
Jack G. Fisher
Author:
Amber D.P. Doyle
Author:
Ben Sale
Author:
Luis Del Rio
Author:
Albert J.E. French
Author:
Neema P. Mayor
Author:
Thomas R. Turner
Author:
Steven G.E. Marsh
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