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Antibody tumor targeting is enhanced by CD27 agonists through myeloid recruitment

Antibody tumor targeting is enhanced by CD27 agonists through myeloid recruitment
Antibody tumor targeting is enhanced by CD27 agonists through myeloid recruitment

Monoclonal antibodies (mAbs) can destroy tumors by recruiting effectors such as myeloid cells, or targeting immunomodulatory receptors to promote cytotoxic T cell responses. Here, we examined the therapeutic potential of combining a direct tumor-targeting mAb, anti-CD20, with an extended panel of immunomodulatory mAbs. Only the anti-CD27/CD20 combination provided cures. This was apparent in multiple lymphoma models, including huCD27 transgenic mice using the anti-huCD27, varlilumab. Detailed mechanistic analysis using single-cell RNA sequencing demonstrated that anti-CD27 stimulated CD8+ T and natural killer cells to release myeloid chemo-attractants and interferon gamma, to elicit myeloid infiltration and macrophage activation. This study demonstrates the therapeutic advantage of using an immunomodulatory mAb to regulate lymphoid cells, which then recruit and activate myeloid cells for enhanced killing of mAb-opsonized tumors.

Journal Article
1535-6108
777-791.e6
Turaj, Anna H.
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Hussain, Khiyam
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Cox, Kerry L.
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Rose-Zerilli, Matthew J.J.
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Testa, James
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Dahal, Lekh N.
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Chan, H.T. Claude
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James, Sonya
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Field, Vikki L.
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Carter, Matthew J.
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Kim, Hyung J.
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West, Jonathan J.
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Thomas, Lawrence J.
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He, Li-Zhen
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Keler, Tibor
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Johnson, Peter W.M.
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Al-Shamkhani, Aymen
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Thirdborough, Stephen M.
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Beers, Stephen A.
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Cragg, Mark S.
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Glennie, Martin J.
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Lim, Sean H.
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Turaj, Anna H.
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Hussain, Khiyam
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Cox, Kerry L.
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Rose-Zerilli, Matthew J.J.
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Testa, James
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Dahal, Lekh N.
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Chan, H.T. Claude
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James, Sonya
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Field, Vikki L.
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Carter, Matthew J.
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Kim, Hyung J.
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West, Jonathan J.
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Thomas, Lawrence J.
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He, Li-Zhen
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Keler, Tibor
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Johnson, Peter W.M.
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Al-Shamkhani, Aymen
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Thirdborough, Stephen M.
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Beers, Stephen A.
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Cragg, Mark S.
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Glennie, Martin J.
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Lim, Sean H.
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Turaj, Anna H., Hussain, Khiyam, Cox, Kerry L., Rose-Zerilli, Matthew J.J., Testa, James, Dahal, Lekh N., Chan, H.T. Claude, James, Sonya, Field, Vikki L., Carter, Matthew J., Kim, Hyung J., West, Jonathan J., Thomas, Lawrence J., He, Li-Zhen, Keler, Tibor, Johnson, Peter W.M., Al-Shamkhani, Aymen, Thirdborough, Stephen M., Beers, Stephen A., Cragg, Mark S., Glennie, Martin J. and Lim, Sean H. (2017) Antibody tumor targeting is enhanced by CD27 agonists through myeloid recruitment. Cancer Cell, 32 (6), 777-791.e6. (doi:10.1016/j.ccell.2017.11.001).

Record type: Article

Abstract

Monoclonal antibodies (mAbs) can destroy tumors by recruiting effectors such as myeloid cells, or targeting immunomodulatory receptors to promote cytotoxic T cell responses. Here, we examined the therapeutic potential of combining a direct tumor-targeting mAb, anti-CD20, with an extended panel of immunomodulatory mAbs. Only the anti-CD27/CD20 combination provided cures. This was apparent in multiple lymphoma models, including huCD27 transgenic mice using the anti-huCD27, varlilumab. Detailed mechanistic analysis using single-cell RNA sequencing demonstrated that anti-CD27 stimulated CD8+ T and natural killer cells to release myeloid chemo-attractants and interferon gamma, to elicit myeloid infiltration and macrophage activation. This study demonstrates the therapeutic advantage of using an immunomodulatory mAb to regulate lymphoid cells, which then recruit and activate myeloid cells for enhanced killing of mAb-opsonized tumors.

Text
Lim Cancer Cell 2017 - Version of Record
Available under License Creative Commons Attribution.
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More information

Accepted/In Press date: 27 November 2017
e-pub ahead of print date: 30 November 2017
Published date: 11 December 2017
Keywords: Journal Article

Identifiers

Local EPrints ID: 416454
URI: http://eprints.soton.ac.uk/id/eprint/416454
ISSN: 1535-6108
PURE UUID: 5b6ab18f-aeec-40b5-8015-ec3058ebd06d
ORCID for Matthew J.J. Rose-Zerilli: ORCID iD orcid.org/0000-0002-1064-5350
ORCID for Jonathan J. West: ORCID iD orcid.org/0000-0002-5709-6790
ORCID for Peter W.M. Johnson: ORCID iD orcid.org/0000-0003-2306-4974
ORCID for Aymen Al-Shamkhani: ORCID iD orcid.org/0000-0003-0727-4189
ORCID for Stephen A. Beers: ORCID iD orcid.org/0000-0002-3765-3342
ORCID for Mark S. Cragg: ORCID iD orcid.org/0000-0003-2077-089X

Catalogue record

Date deposited: 19 Dec 2017 09:45
Last modified: 16 Nov 2021 02:47

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Contributors

Author: Anna H. Turaj
Author: Khiyam Hussain
Author: Kerry L. Cox
Author: James Testa
Author: Lekh N. Dahal
Author: H.T. Claude Chan
Author: Sonya James
Author: Vikki L. Field
Author: Hyung J. Kim
Author: Lawrence J. Thomas
Author: Li-Zhen He
Author: Tibor Keler
Author: Mark S. Cragg ORCID iD
Author: Sean H. Lim

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