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

Sarah L Buchan, Mohannah Fallatah, Stephen M Thirdborough, Vadim Taraban, Anne Rogel, Lawrence J Thomas, Christine A Penfold, Li-Zhen He, Michael A Curran, Tibor Keler, Aymen Al-Shamkhani

Research output: Contribution to journalArticle

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-γ, 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 co-operate for CD8+ T-cell activation.

Original languageEnglish
Pages (from-to)2383-2394
Number of pages12
JournalClinical Cancer Research
Volume24
Issue number10
DOIs
Publication statusPublished - 15 May 2018

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Immunity
T-Lymphocytes
Monoclonal Antibodies
Neoplasms
Dendritic Cells
Granzymes
Adoptive Transfer
Gene Expression Profiling
Immunotherapy
Transgenic Mice
Interleukin-2
Lymphoma
Flow Cytometry
Therapeutics
Gene Expression

Cite this

Buchan, Sarah L ; Fallatah, Mohannah ; Thirdborough, Stephen M ; Taraban, Vadim ; Rogel, Anne ; Thomas, Lawrence J ; Penfold, Christine A ; He, Li-Zhen ; Curran, Michael A ; Keler, Tibor ; Al-Shamkhani, Aymen. / PD-1 blockade and CD27 stimulation activate distinct transcriptional programs that synergize for CD8+ T-cell driven anti-tumor immunity. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 10. pp. 2383-2394.
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title = "PD-1 blockade and CD27 stimulation activate distinct transcriptional programs that synergize for CD8+ T-cell driven anti-tumor immunity",
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-γ, 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 co-operate for CD8+ T-cell activation.",
author = "Buchan, {Sarah L} and Mohannah Fallatah and Thirdborough, {Stephen M} and Vadim Taraban and Anne Rogel and Thomas, {Lawrence J} and Penfold, {Christine A} and Li-Zhen He and Curran, {Michael A} and Tibor Keler and Aymen Al-Shamkhani",
note = "Copyright {\circledC}2018, American Association for Cancer Research.",
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Buchan, SL, Fallatah, M, Thirdborough, SM, Taraban, V, Rogel, A, Thomas, LJ, Penfold, CA, He, L-Z, Curran, MA, Keler, T & Al-Shamkhani, A 2018, 'PD-1 blockade and CD27 stimulation activate distinct transcriptional programs that synergize for CD8+ T-cell driven anti-tumor immunity' Clinical Cancer Research, vol. 24, no. 10, pp. 2383-2394. https://doi.org/10.1158/1078-0432.CCR-17-3057

PD-1 blockade and CD27 stimulation activate distinct transcriptional programs that synergize for CD8+ T-cell driven anti-tumor immunity. / Buchan, Sarah L; Fallatah, Mohannah; Thirdborough, Stephen M; Taraban, Vadim; Rogel, Anne; Thomas, Lawrence J; Penfold, Christine A; He, Li-Zhen; Curran, Michael A; Keler, Tibor; Al-Shamkhani, Aymen.

In: Clinical Cancer Research, Vol. 24, No. 10, 15.05.2018, p. 2383-2394.

Research output: Contribution to journalArticle

TY - JOUR

T1 - PD-1 blockade and CD27 stimulation activate distinct transcriptional programs that synergize for CD8+ T-cell driven anti-tumor immunity

AU - Buchan, Sarah L

AU - Fallatah, Mohannah

AU - Thirdborough, Stephen M

AU - Taraban, Vadim

AU - Rogel, Anne

AU - Thomas, Lawrence J

AU - Penfold, Christine A

AU - He, Li-Zhen

AU - Curran, Michael A

AU - Keler, Tibor

AU - Al-Shamkhani, Aymen

N1 - Copyright ©2018, American Association for Cancer Research.

PY - 2018/5/15

Y1 - 2018/5/15

N2 - 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-γ, 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 co-operate for CD8+ T-cell activation.

AB - 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-γ, 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 co-operate for CD8+ T-cell activation.

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U2 - 10.1158/1078-0432.CCR-17-3057

DO - 10.1158/1078-0432.CCR-17-3057

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EP - 2394

JO - Clinical Cancer Research

JF - Clinical Cancer Research

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