TY - JOUR
T1 - Pd-1 blockade and cd27 stimulation activate distinct transcriptional programs that synergize for CD8þ T-cell–driven antitumor immunity
AU - Buchan, Sarah L.
AU - Fallatah, Mohannad
AU - Thirdborough, Stephen M.
AU - Taraban, Vadim Y.
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 - Publisher 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 (DC). 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 CD8þ T-cell expansion and effector function, exemplified by enhanced IFNg, TNFa, granzyme B, and T-bet. Transcriptome analysis of CD8þ T cells revealed that combination therapy triggered a convergent program largely driven by IL2 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 CD8þ T cells or adoptive transfer of transgenic T cells, anti-CD27 mAb synergized with PD-1/L1 blockade for antitumor 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 CD8þ 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 (DC). 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 CD8þ T-cell expansion and effector function, exemplified by enhanced IFNg, TNFa, granzyme B, and T-bet. Transcriptome analysis of CD8þ T cells revealed that combination therapy triggered a convergent program largely driven by IL2 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 CD8þ T cells or adoptive transfer of transgenic T cells, anti-CD27 mAb synergized with PD-1/L1 blockade for antitumor 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 CD8þ T-cell activation.
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U2 - 10.1158/1078-0432.CCR-17-3057
DO - 10.1158/1078-0432.CCR-17-3057
M3 - Article
C2 - 29514845
AN - SCOPUS:85047835676
SN - 1078-0432
VL - 24
SP - 2383
EP - 2394
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 10
ER -