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Therapeutic Efficacy of 4-1BB Costimulation Is Abrogated by PD-1 Blockade in a Model of Spontaneous B-cell Lymphoma

Sara J. McKee, Brianna L. Doff, Megan S.F. Soon and Stephen R. Mattarollo
Sara J. McKee
The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
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Brianna L. Doff
The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
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Megan S.F. Soon
The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
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Stephen R. Mattarollo
The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
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  • For correspondence: s.mattarollo@uq.edu.au
DOI: 10.1158/2326-6066.CIR-16-0249 Published March 2017
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    Figure 1.

    Efficacy of vaccine with and without 4-1BB mAb to inhibit the development of lymphoma in Eμ-myc transgenic mice. A, Schematic of treatment schedule. B, Survival of Eμ-myc transgenic mice that received irradiated tumour cell vaccine or 4-1BB mAb, either alone or in combination. Shaded gray box, age at initiation of treatment. C, IFNγ production and CD69 expression on NK, NKT, and CD8+ T cells in the blood 24 hours after receiving vaccine. ND, not detected. D, Numbers of CD8+ T cells and proportion of CD8+ T cells expressing CD44 in the blood at 6.7 to 7 weeks after initiation of treatment. ns, not significant. Statistics: log-rank (Mantel–Cox) test (B), Mann–Whitney t test (C), one-way ANOVA with Holm–Sidak multiple comparison test (D). *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001. Data shown are from a single experiment.

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    Figure 2.

    Generation of a protective antilymphoma memory response in long-term Eμ-myc survivors. A, Individual mouse tumor growth curves for GFP+ Eμ-myc 299 in Eμ-myc transgenic mice that were initially untreated, or had received either 4-1BB mAb or vaccine + 4-1BB mAb >25 weeks earlier. B, Mean GFP+ Eμ-myc 299 tumor burden ± SEM over time and at 14 days after Eμ-myc 299 tumor inoculation. ns, not significant. C, Representative dot plots of tumor burden (top); KLRG1 expression on activated CD8 T cells (bottom) 14 days after tumor inoculation. Statistics: one-way ANOVA with Dunn multiple comparison test (B). *, P < 0.05; ***, P < 0.001.

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    Figure 3.

    PD-1 blockade abrogated the protective antitumor effect induced by 4-1BB mAb. A, PD-1 expression on CD8+ T cells in untreated Eμ-myc transgenic mice or 20 weeks after 4-1BB mAb treatment. MFI, mean fluorescence intensity. B, Survival of Eμ-myc transgenic mice that received 4-1BB mAb or PD-1 mAb, either alone or in combination. Shaded gray box, age at initiation of treatment (RX). ns, not significant. C, Percent of CD8+ T cells in the blood that are CD44+ CD62L− (TEM) or CD44+ CD62L− (TCM) after 4-1BB mAb or PD-1 mAb, either alone or in combination. Lines, individual mice. Statistics: log-rank (Mantel–Cox) test (B). *, P < 0.05. Data compiled from sequential cohorts of treated mice.

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    Figure 4.

    PD-1 blockade abrogated the expansion of activated memory cells induced by 4-1BB mAb. A, Number of activated CD8+ CD44+ cells in the blood of Eμ-myc transgenic mice after vaccine, 4-1BB mAb, or PD-1 mAb either alone or in combination. Shaded gray box, two treatment cycles. B, Percent of CD8+ T cells that are KLRG1+ CD127− (SLEC) or KLRG1+ CD127+ (DPEC) after vaccine, 4-1BB mAb, or PD-1 mAb, either alone or in combination. ns, not significant. C, Representative dot plots of KLRG1 and CD127 expression on CD8+ T cells after vaccine, 41BB mAb, or PD-1 mAb, either alone or in combination. Statistics:one-way ANOVA with Dunnett multiple comparison test (B). *, P < 0.05; **, P < 0.01; ***, P < 0.001, ****, P < 0.0001.

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Cancer Immunology Research: 5 (3)
March 2017
Volume 5, Issue 3
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Therapeutic Efficacy of 4-1BB Costimulation Is Abrogated by PD-1 Blockade in a Model of Spontaneous B-cell Lymphoma
Sara J. McKee, Brianna L. Doff, Megan S.F. Soon and Stephen R. Mattarollo
Cancer Immunol Res March 1 2017 (5) (3) 191-197; DOI: 10.1158/2326-6066.CIR-16-0249

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Therapeutic Efficacy of 4-1BB Costimulation Is Abrogated by PD-1 Blockade in a Model of Spontaneous B-cell Lymphoma
Sara J. McKee, Brianna L. Doff, Megan S.F. Soon and Stephen R. Mattarollo
Cancer Immunol Res March 1 2017 (5) (3) 191-197; DOI: 10.1158/2326-6066.CIR-16-0249
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