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Molecular Cancer Therapeutics
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Large Molecule Therapeutics

Herpes Simplex Virus Glycoprotein D Targets a Specific Dendritic Cell Subset and Improves the Performance of Vaccines to Human Papillomavirus-Associated Tumors

Bruna F.M.M. Porchia, Ana Carolina R. Moreno, Rodrigo N. Ramos, Mariana O. Diniz, Laís Helena T.M. de Andrade, Daniela S. Rosa, José Alexandre M. Barbuto, Silvia B. Boscardin and Luís Carlos S. Ferreira
Bruna F.M.M. Porchia
1Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
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Ana Carolina R. Moreno
1Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
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Rodrigo N. Ramos
2Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
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Mariana O. Diniz
1Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
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Laís Helena T.M. de Andrade
1Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
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Daniela S. Rosa
3Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo-UNIFESP, São Paulo, Brazil.
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José Alexandre M. Barbuto
2Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
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Silvia B. Boscardin
4Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
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Luís Carlos S. Ferreira
1Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
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  • For correspondence: lcsf@usp.br
DOI: 10.1158/1535-7163.MCT-17-0071 Published September 2017
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    Figure 1.

    Co-administration of poly (I:C) enhances the antitumor effects and activation of E7-specific cytotoxic responses in mice immunized with gDE7. A, Enhanced antitumor effects in mice immunized with gDE7 admixed with poly (I:C). Mice were challenged with 7.5 × 104 TC-1 cells and immunized with two subcutaneous doses (days 1 and 8 after challenge, indicated by arrows) of gDE7 or E7 proteins admixed or not with poly (I:C). *, P < 0.05 versus all other immunization groups. Data are based on 5 mice per group from 1 of 2 independent experiments with similar results. B, Antitumor effects induced by immunization with gDE7 admixed with poly (I:C) are kept even when the interval between transplantation of the TC-1 cells and the first dose is increased. The first immunization dose occurred 1, 3, 5, 7, or 10 days after transplantation of TC-1 cells, and the boost was given 7 days after the prime dose. Mice were followed for 60 days for tumor growth assessment. Data are based on 5 mice per group from 1 of 2 independent experiments with similar results. C, Induction of IFNγ-producing CD8+ T cells after immunization with gDE7 or E7 admixed or not with poly (I:C). The frequencies of IFNγ-producing E7-specific CD8+ T cells were determined in mice challenged with TC-1 cells and immunized with two subcutaneous doses (indicated by arrows) of the different formulations. Data represent the mean ± SD of 5 mice per group from 1 of 2 independent experiments with similar results. D, In vivo cytotoxic activity induced in mice immunized with two subcutaneous doses of tested vaccine formulations (days 1 and 8 after challenge). Percentage of cell death mediated by E7-specific CD8+ T cells after injection of 107 target cells in mice submitted to different immunization procedures. *, P < 0.05; ***, P < 0.001. Data represent the mean of 5 mice per group from 1 of 2 independent experiments with similar results.

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    Figure 2.

    Immunization with gDE7 admixed with poly (I:C) induces activation of multifunctional and effector memory CD8+ T cells. A–E, Immunizations with gDE7 admixed with poly (I:C) induce the differentiation of multifunctional CD8+ T cells. Mice were immunized with two subcutaneous doses of gDE7 or E7 admixed or not with poly (I:C) on days 1 and 8 after challenge. Spleen cells were analyzed by flow cytometry 14 days after the last immunization. A, Multiparametric flow cytometry of multifunctional CD8+ T cells. The frequencies of IFNγ (B), TNFα (C), or IL2 (D) single producers CD8+ T cells were depicted. *, P < 0.05; **, P < 0.01; ***, P < 0.001. E, After gating on CD8+ T cells, Boolean combinations were created using the FlowJo software to determine the frequency of all possible combinations of cytokine production. *, P < 0.05 versus all other experimental groups in IL2-producing CD8+ T cells; **, P < 0.01 versus all other experimental groups in IFNγ -and TNFα-producing CD8+ T cells. Data represent the mean ± SD of 4–5 mice per group from 1 of 2 independent experiments with similar results. F, Administration of gDE7 admixed with poly (I:C) induces the differentiation of effector memory E7-specific CD8+ T cells. Spleen cells from challenged and immunized mice were labeled with an E7 H-2Db–specific dextramer and subjected to phenotypic analysis using CD44 and CD62L T-cell markers by flow cytometry. Effector memory (CD44+CD62Llow) and central memory (CD44+CD62Lhigh) CD8+ T-cell ratio in mice challenged with TC-1 cells and subsequently immunized with two doses (days 1 and 8 post-challenge) of tested vaccine formulations. ***, P < 0.001; •, P < 0.05 versus all other experimental groups in TEM. Data represent the mean ± SD of 4–5 mice per group from 1 of 2 independent experiments with similar results. G and H, Immunization with gDE7 admixed with poly (I:C) induces high frequency of tumor-infiltrating E7-specific CD8+ T cells. Mice were challenged with 7.5 × 104 TC-1 cells suspended in Matrigel and were immunized with two subcutaneous doses (days 1 and 8 after challenge) of tested vaccine formulations. Four days after the last dose, mice were euthanized, and tumors/Matrigel were removed for tumor microenvironment analysis by flow cytometry. G, Frequencies of tumor-infiltrating CD8+ T cells induced by the tested vaccine formulations. H, Cells recovered from tumors/Matrigel of E7 admixed with poly (I:C), gDE7, and gDE7 admixed with poly (I:C) immunized mice were labeled with an E7 H-2Db–specific dextramer, and the frequencies of tumor-infiltrating E7-specific CD8+ T cells were determined. ***, P < 0.001 versus all other experimental groups. Data represent the mean ± SD of 4 mice per group from 1 of 2 independent experiments with similar results.

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    Figure 3.

    Control of tumor development mediated by gDE7 admixed with poly (I:C) vaccine formulation prevents expansion of splenic immunosuppressive cells. For immunosuppressive cells analysis, mice were challenged with 7.5 × 104 TC-1 cells and immunized with two subcutaneous doses (days 1 and 8 after challenge) of gDE7 or E7 admixed or not with poly (I:C). A and B, Spleen Treg cells do not expand in mice immunized with gDE7-based antitumor vaccines. For Treg analysis, spleen cells were incubated with 10 μg/mL of E7 protein for 5 days. After the incubation time, spleen cells were stained with anti-CD4, anti-CD25, and anti-Foxp3, and the frequency of Treg cells was determined. Numbers inside plots represent the frequency of CD25+Foxp3+ cells over all CD4+ T cells of a representative mouse. **, P < 0.01. Data represent the mean ± SD of 5 mice per group from 1 of 2 independent experiments with similar results. C and D, Spleen MDSCs do not expand in mice challenged with TC-1 cells and immunized with gDE7-based antitumor vaccines. Spleen cells from challenged and immunized mice were stained with anti-CD45, anti-CD11b, and anti-Gr-1 antibodies, and the frequency of MDSCs is depicted. Numbers inside plots represent the frequency of CD11b+ Gr-1+ over all CD45+ cells of a representative mouse. **, P < 0.01. Data represent the mean ± SD of 5 mice per group of 1 of 2 independent experiments with similar results.

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    Figure 4.

    Targeting of gDE7 to mouse CD11c+ CD8α+ DC leads to DC activation. gD and gDE7 recombinant proteins bind with higher affinity to mouse DC subset specialized in antigen cross-presentation. A, Gating strategy for analysis of gD, gDE7, or E7 binding and activation of isolated mouse DCs. Doublets and CD3+/CD19+/CD49b+ cells were excluded from analysis. CD11c+MHC-II+ cells were gated and subsequently separated by the expression of CD8α+. B, Isolated mouse DCs (4 × 105 cells/well) were incubated with gD, gDE7, or E7 proteins at equimolar amounts. Protein binding was detected in 105 cells using mouse anti-His tag and anti-mouse IgG-PE monoclonal antibodies. C, MFI of protein binding on CD11c+ CD8α+ and CD11c+ CD8α− DCs. ***, P < 0.001; •, P < 0.05; and •••, P < 0.001 versus E7 on CD11c+ CD8α+ DCs; ###, P < 0.001 versus E7 on CD11c+ CD8α− DCs. Data represent the mean of triplicate assays ± SD of 1 of 2 independent experiments with similar results. gD and gDE7 recombinant proteins promote activation of mouse DCs specialized in antigen cross-presentation. DC activation was determined by upregulation of surface molecules and intracellular cytokine production. MFI of CD40 (D) and CD86 (E) and IL12 production (F) on CD11c+ CD8α+ and CD11c+ CD8α− DCs. ***, P < 0.001; ••, P < 0.01; and •••, P < 0.001 versus E7 on CD11c+ CD8α+ DCs; #, P < 0.05 versus E7 on CD11c+ CD8α− DCs. ★, P < 0.05 versus iDC. Data represent the mean of duplicate assays ± SD of 1 of 2 independent experiments with similar results. iDC, cells incubated with apyrogenic saline.

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    Figure 5.

    gDE7 protein activates human DCs specialized in antigen cross-presentation. A, Gating strategy for activation analysis of human Mo-DCs and blood DCs mediated by gD, gDE7, or E7 proteins. The activation of human DCs was induced by equimolar amounts of gD, gDE7, and E7 recombinant proteins and analyzed by TNFα production (B). Data represent the mean ± SE of 3 healthy donors considered as 3 independent experiments. *, P < 0.05; **, P < 0.01. ns, not statistically significant. DC, cells incubated with apyrogenic saline.

Additional Files

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    • Figure S1 - Figure S1. Immunization with gDE7 admixed with poly (I:C) induces full therapeutic antitumor protection in WT, TLR4 KO and CD4+ T cells KO mice.
    • Figure S2 - Figure S2. Polymixin B inhibits LPS-induced up-regulation of co-stimulatory molecules and secretion of inflammatory cytokines in both mouse and human DCs.
    • Figure S1 and S2 Legends - Figure S1 and S2 Legends
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Molecular Cancer Therapeutics: 16 (9)
September 2017
Volume 16, Issue 9
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Herpes Simplex Virus Glycoprotein D Targets a Specific Dendritic Cell Subset and Improves the Performance of Vaccines to Human Papillomavirus-Associated Tumors
Bruna F.M.M. Porchia, Ana Carolina R. Moreno, Rodrigo N. Ramos, Mariana O. Diniz, Laís Helena T.M. de Andrade, Daniela S. Rosa, José Alexandre M. Barbuto, Silvia B. Boscardin and Luís Carlos S. Ferreira
Mol Cancer Ther September 1 2017 (16) (9) 1922-1933; DOI: 10.1158/1535-7163.MCT-17-0071

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Herpes Simplex Virus Glycoprotein D Targets a Specific Dendritic Cell Subset and Improves the Performance of Vaccines to Human Papillomavirus-Associated Tumors
Bruna F.M.M. Porchia, Ana Carolina R. Moreno, Rodrigo N. Ramos, Mariana O. Diniz, Laís Helena T.M. de Andrade, Daniela S. Rosa, José Alexandre M. Barbuto, Silvia B. Boscardin and Luís Carlos S. Ferreira
Mol Cancer Ther September 1 2017 (16) (9) 1922-1933; DOI: 10.1158/1535-7163.MCT-17-0071
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