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A peptide: MHC based DNA vaccination strategy to activate natural killer cells by targeting killer cell immunoglobulin-like receptors.

A peptide: MHC based DNA vaccination strategy to activate natural killer cells by targeting killer cell immunoglobulin-like receptors.
A peptide: MHC based DNA vaccination strategy to activate natural killer cells by targeting killer cell immunoglobulin-like receptors.

Background Natural killer (NK) cells are increasingly being recognized as agents for cancer immunotherapy. The killer cell immunoglobulin-like receptors (KIRs) are expressed by NK cells and are immunogenetic determinants of the outcome of cancer. In particular, KIR2DS2 is associated with protective responses to several cancers and also direct recognition of cancer targets in vitro. Due to the high homology between activating and inhibitory KIR genes to date, it has been challenging to target individual KIR for therapeutic benefit. Methods A novel KIR2DS2-targeting therapeutic peptide:MHC DNA vaccine was designed and used to immunize mice transgenic for KIR genes (KIR-Tg). NK cells were isolated from the livers and spleens of vaccinated mice and then analyzed for activation by flow cytometry, RNA profiling and cytotoxicity assays. In vivo assays of NK cell function using a syngeneic cancer model (B16 melanoma) and an adoptive transfer model for human hepatocellular carcinoma (Huh7) were performed. Results Injecting KIR-Tg mice with the vaccine construct activated NK cells in both liver and spleens of mice, with preferential activation of KIR2DS2-positive NK cells. KIR-specific activation was most marked on the CD11b+CD27+ mature subset of NK cells. RNA profiling indicated that the DNA vaccine upregulated genes associated with cellular metabolism and downregulated genes related to histone H3 methylation, which are associated with immune cell maturation and NK cell function. Vaccination led to canonical and cross-reactive peptide:MHC-specific NK cell responses. In vivo, DNA vaccination led to enhanced antitumor responses against B16F10 melanoma cells and also enhanced responses against a tumor model expressing the KIR2DS2 ligand HLA-C∗0102. Conclusion We show the feasibility of a peptide-based KIR-targeting vaccine strategy to activate NK cells and hence generate functional antitumor responses. This approach does not require detailed knowledge of the tumor peptidomes nor HLA matching with the patient. It therefore offers a novel opportunity for targeting NK cells for cancer immunotherapy.

immunity, immunogenicity, innate, killer cells, natural, vaccine
Khakoo, Salim
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Rettman, Pauline E
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Blunt, Matthew
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Fulton, Rebecca
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Vallejo Pulido, Andres
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Bastidas Legarda, Leidy
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Espana-Serrano, Laura
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Polak, Marta
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Al-Shamkhani, Aymen
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Retiere, Christelle
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Khakoo, Salim
6c16d2f5-ae80-4d9b-9100-6bfb34ad0273
Rettman, Pauline E
d761e696-6680-4168-931d-4586a6062a58
Blunt, Matthew
b1109de3-6045-4bc3-bd77-6cf26504697d
Fulton, Rebecca
848aa9dc-797f-40f8-b63d-bca0d90f7b55
Vallejo Pulido, Andres
27bc0b94-0c40-4fd1-9533-7e267d588c0a
Bastidas Legarda, Leidy
66bd5603-1c85-4321-a129-20ced5b35e4c
Espana-Serrano, Laura
3728289d-df32-4afc-8b85-5478054f1c29
Polak, Marta
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Al-Shamkhani, Aymen
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Retiere, Christelle
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Khakoo, Salim, Rettman, Pauline E, Blunt, Matthew, Fulton, Rebecca, Vallejo Pulido, Andres, Bastidas Legarda, Leidy, Espana-Serrano, Laura, Polak, Marta, Al-Shamkhani, Aymen and Retiere, Christelle (2021) A peptide: MHC based DNA vaccination strategy to activate natural killer cells by targeting killer cell immunoglobulin-like receptors. Journal for Immunotherapy of Cancer, 9 (5), [e001912]. (doi:10.1136/jitc-2020-001912).

Record type: Article

Abstract

Background Natural killer (NK) cells are increasingly being recognized as agents for cancer immunotherapy. The killer cell immunoglobulin-like receptors (KIRs) are expressed by NK cells and are immunogenetic determinants of the outcome of cancer. In particular, KIR2DS2 is associated with protective responses to several cancers and also direct recognition of cancer targets in vitro. Due to the high homology between activating and inhibitory KIR genes to date, it has been challenging to target individual KIR for therapeutic benefit. Methods A novel KIR2DS2-targeting therapeutic peptide:MHC DNA vaccine was designed and used to immunize mice transgenic for KIR genes (KIR-Tg). NK cells were isolated from the livers and spleens of vaccinated mice and then analyzed for activation by flow cytometry, RNA profiling and cytotoxicity assays. In vivo assays of NK cell function using a syngeneic cancer model (B16 melanoma) and an adoptive transfer model for human hepatocellular carcinoma (Huh7) were performed. Results Injecting KIR-Tg mice with the vaccine construct activated NK cells in both liver and spleens of mice, with preferential activation of KIR2DS2-positive NK cells. KIR-specific activation was most marked on the CD11b+CD27+ mature subset of NK cells. RNA profiling indicated that the DNA vaccine upregulated genes associated with cellular metabolism and downregulated genes related to histone H3 methylation, which are associated with immune cell maturation and NK cell function. Vaccination led to canonical and cross-reactive peptide:MHC-specific NK cell responses. In vivo, DNA vaccination led to enhanced antitumor responses against B16F10 melanoma cells and also enhanced responses against a tumor model expressing the KIR2DS2 ligand HLA-C∗0102. Conclusion We show the feasibility of a peptide-based KIR-targeting vaccine strategy to activate NK cells and hence generate functional antitumor responses. This approach does not require detailed knowledge of the tumor peptidomes nor HLA matching with the patient. It therefore offers a novel opportunity for targeting NK cells for cancer immunotherapy.

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rettman et al - Accepted Manuscript
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Accepted/In Press date: 8 April 2021
e-pub ahead of print date: 20 May 2021
Published date: 20 May 2021
Keywords: immunity, immunogenicity, innate, killer cells, natural, vaccine

Identifiers

Local EPrints ID: 449652
URI: http://eprints.soton.ac.uk/id/eprint/449652
PURE UUID: d126a14a-8b6e-414a-b72e-c89846efdf80
ORCID for Andres Vallejo Pulido: ORCID iD orcid.org/0000-0002-4688-0598
ORCID for Aymen Al-Shamkhani: ORCID iD orcid.org/0000-0003-0727-4189

Catalogue record

Date deposited: 10 Jun 2021 16:31
Last modified: 26 Nov 2021 03:10

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Contributors

Author: Salim Khakoo
Author: Pauline E Rettman
Author: Matthew Blunt
Author: Rebecca Fulton
Author: Andres Vallejo Pulido ORCID iD
Author: Leidy Bastidas Legarda
Author: Laura Espana-Serrano
Author: Marta Polak
Author: Christelle Retiere

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