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PD-1 blockade and CD27 stimulation activate distinct transcriptional programs that synergize for CD8+ T-cell driven anti-tumor immunity

PD-1 blockade and CD27 stimulation activate distinct transcriptional programs that synergize for CD8+ T-cell driven anti-tumor immunity
PD-1 blockade and CD27 stimulation activate distinct transcriptional programs that synergize for CD8+ T-cell driven anti-tumor immunity
Purpose: PD-1 checkpoint blockade has revolutionized the field of cancer immunotherapy, yet the frequency of responding patients is limited by inadequate T-cell priming secondary to a paucity of activatory dendritic cells (DCs). DC signals can be bypassed by CD27 agonists and we therefore investigated if the effectiveness of anti-PD-1/L1 could be improved by
combining with agonist anti-CD27 monoclonal antibodies (mAb).

Experimental Design: the efficacy of PD-1/L1 blockade or agonist anti-CD27 mAb was compared with a dual-therapy approach in multiple tumor models. Global transcriptional profiling and flow-cytometry analysis were used to delineate mechanisms underpinning the observed synergy.

Results: PD-1/PD-L1 blockade and agonist anti-CD27 mAb synergize for increased CD8+ T-cell expansion and effector function, exemplified by enhanced IFN-, TNF-α, granzyme B and T-bet. Transcriptome analysis of CD8+ T cells revealed that combination therapy triggered a convergent program largely driven by IL-2 and Myc. However, division of labor was also apparent such that anti-PD-1/L1 activates a cytotoxicity-gene expression program whereas anti-CD27 preferentially augments proliferation. In tumor models, either dependent on endogenous CD8+ T cells or adoptive transfer of transgenic T cells, anti-CD27 mAb synergized with PD-1/L1 blockade for anti-tumor immunity. Finally, we show that a clinically-relevant anti-human CD27 mAb, varlilumab, similarly synergizes with PD-L1 blockade for protection against lymphoma in human-CD27 transgenic mice.

Conclusions: our findings suggest that suboptimal T-cell invigoration in cancer patients undergoing treatment with PD-1 checkpoint blockers will be improved by dual PD-1 blockade and CD27 agonism and provide mechanistic insight into how these approaches cooperate for CD8+ T-cell activation.
1078-0432
2383-2394
Buchan, Sarah
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Fallatah, Mohannad
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Thirdborough, Stephen
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Taraban, Vadim Y.
d709dcbb-ff36-4514-85da-08ca68aafcd3
Rogel, Anne
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Thomas, Lawrence J.
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Penfold, Christine
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He, Li-Zhen
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Curran, Michael
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Keler, Tibor
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Al-Shamkhani, Aymen
0a40b3ce-9d71-4d41-9369-7212f0a84504
Buchan, Sarah
9ade187d-f127-45de-ad90-9d544d64718a
Fallatah, Mohannad
bb9755d4-3a4c-4b3e-b2cd-b45a743e42da
Thirdborough, Stephen
161784fb-c8e3-4beb-86b1-cd8bc8ddf8de
Taraban, Vadim Y.
d709dcbb-ff36-4514-85da-08ca68aafcd3
Rogel, Anne
5a895ba8-c877-484f-a9c1-34a2b1af6414
Thomas, Lawrence J.
fac67673-3e53-400a-8282-630293646313
Penfold, Christine
400d743e-a639-45ea-a027-5b778800f6d3
He, Li-Zhen
867c52b8-34d4-46b2-a59f-0b6801f827d2
Curran, Michael
03ea473d-f92d-4f2b-a30f-1510986ddfa8
Keler, Tibor
38add6e3-58be-4bc4-a9df-ba10c9e1ae1e
Al-Shamkhani, Aymen
0a40b3ce-9d71-4d41-9369-7212f0a84504

Buchan, Sarah, Fallatah, Mohannad, Thirdborough, Stephen, Taraban, Vadim Y., Rogel, Anne, Thomas, Lawrence J., Penfold, Christine, He, Li-Zhen, Curran, Michael, Keler, Tibor and Al-Shamkhani, Aymen (2018) PD-1 blockade and CD27 stimulation activate distinct transcriptional programs that synergize for CD8+ T-cell driven anti-tumor immunity. Clinical Cancer Research, 24 (10), 2383-2394. (doi:10.1158/1078-0432.CCR-17-3057).

Record type: Article

Abstract

Purpose: PD-1 checkpoint blockade has revolutionized the field of cancer immunotherapy, yet the frequency of responding patients is limited by inadequate T-cell priming secondary to a paucity of activatory dendritic cells (DCs). DC signals can be bypassed by CD27 agonists and we therefore investigated if the effectiveness of anti-PD-1/L1 could be improved by
combining with agonist anti-CD27 monoclonal antibodies (mAb).

Experimental Design: the efficacy of PD-1/L1 blockade or agonist anti-CD27 mAb was compared with a dual-therapy approach in multiple tumor models. Global transcriptional profiling and flow-cytometry analysis were used to delineate mechanisms underpinning the observed synergy.

Results: PD-1/PD-L1 blockade and agonist anti-CD27 mAb synergize for increased CD8+ T-cell expansion and effector function, exemplified by enhanced IFN-, TNF-α, granzyme B and T-bet. Transcriptome analysis of CD8+ T cells revealed that combination therapy triggered a convergent program largely driven by IL-2 and Myc. However, division of labor was also apparent such that anti-PD-1/L1 activates a cytotoxicity-gene expression program whereas anti-CD27 preferentially augments proliferation. In tumor models, either dependent on endogenous CD8+ T cells or adoptive transfer of transgenic T cells, anti-CD27 mAb synergized with PD-1/L1 blockade for anti-tumor immunity. Finally, we show that a clinically-relevant anti-human CD27 mAb, varlilumab, similarly synergizes with PD-L1 blockade for protection against lymphoma in human-CD27 transgenic mice.

Conclusions: our findings suggest that suboptimal T-cell invigoration in cancer patients undergoing treatment with PD-1 checkpoint blockers will be improved by dual PD-1 blockade and CD27 agonism and provide mechanistic insight into how these approaches cooperate for CD8+ T-cell activation.

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190826_2_merged_1519135323 - Accepted Manuscript
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Accepted/In Press date: 2 March 2018
e-pub ahead of print date: 7 March 2018
Published date: May 2018

Identifiers

Local EPrints ID: 418679
URI: https://eprints.soton.ac.uk/id/eprint/418679
ISSN: 1078-0432
PURE UUID: 4c6e4f64-2680-462b-9a83-72e0d4042f37
ORCID for Aymen Al-Shamkhani: ORCID iD orcid.org/0000-0003-0727-4189

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Date deposited: 16 Mar 2018 17:30
Last modified: 14 Mar 2019 05:12

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Contributors

Author: Sarah Buchan
Author: Mohannad Fallatah
Author: Vadim Y. Taraban
Author: Anne Rogel
Author: Lawrence J. Thomas
Author: Christine Penfold
Author: Li-Zhen He
Author: Michael Curran
Author: Tibor Keler

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