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TUSC2 Immunogene Therapy Synergizes with Anti–PD-1 through Enhanced Proliferation and Infiltration of Natural Killer Cells in Syngeneic Kras-Mutant Mouse Lung Cancer Models

Ismail M. Meraz, Mourad Majidi, Xiaobo Cao, Heather Lin, Lerong Li, Jing Wang, Veera Baladandayuthapani, David Rice, Boris Sepesi, Lin Ji and Jack A. Roth
Ismail M. Meraz
1Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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  • For correspondence: imeraz@mdanderson.org
Mourad Majidi
1Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Xiaobo Cao
1Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Heather Lin
2Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Lerong Li
3Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Jing Wang
3Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Veera Baladandayuthapani
2Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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David Rice
1Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Boris Sepesi
1Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Lin Ji
1Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Jack A. Roth
1Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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DOI: 10.1158/2326-6066.CIR-17-0273 Published February 2018
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    Figure 1.

    TUSC2 + anti–PD-1 treatment enhanced antitumor activity. A, Sequential treatment strategy. B, Surface expression PD-L1 on CMT167-luc cells determined by flow cytometry. C and D, Tumor growth curves for four different treatment groups (n = 10 mice/group) were determined based on tumor volume and bioluminescence intensity generated by IVIS 200. Control group was treated with nanovesicles loaded with empty vector. E, Representative IVIS images of tumor-bearing mice. The data are representative of four independent experiments. *, P < 0.05; **, P < 0.01; ***, P < 0.001.

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    Figure 2.

    Combined TUSC2 and anti–PD-1 upregulates NK and cytotoxic T cells and downregulates regulatory cells. A, Effect of TUSC2 on peripheral NK, T cells, and B cells in tumor-free mice. Pooled samples of n = 3 mice/group. In vivo uptake of TUSC2 nanovesicles determined based on exogenous TUSC2 expression by RT-PCR in sorted T, B, NK, and lineage-negative cells. B, Effect of treatments on NK, T, and B cells at week 2 of tumor implantation. C, TUSC2 treatment altered MDSC status. Gating strategy for MDSC; CD45+>CD3–>MHCIIlow>CD11b+>Gr-1+. Granulocytic MDSC: CD11b+Gr-1high and monocytic MDSC: CD11b+Gr-1low. D, Effect of treatment on Tregs (CD4+CD25+). E, Surface expression of PD-1, CTLA-4, and Tim-3 on T cells. F, Effect on ratios of NK/MDSC and CD8+ T cells/Tregs. Data shown as mean ± SD; n = 5; *, P < 0.05; **, P < 0.01; ***, P < 0.001.

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    Figure 3.

    TUSC2 combination increased infiltration of NK and CD8 T cells and impeded MDSCs and Tregs. A, Immunohistochemistry images for formalin fixed tumor. Vectra automated imaging system was used to take high-resolution images (20×) with imaging of 25% of the tumor area. n = 5 tumor sections/groups were imaged. Approximately 100 images per treatment group were analyzed by InForm software for H-Scoring. *, P < 0.05; **, P < 0.01; ***, P < 0.001. B, Chemokine gene expression analysis in tumor samples (n = 3/treatment) shown and determined by NanoString technology. C, Concentration of CCL4 and CCL5 chemokines in serum induced by TUSC2 treatment are shown. Mean ± SD; n = 3; ***, P < 0.001.

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    Figure 4.

    Dependence of the antitumor activity of TUSC2 on NK cells. Antitumor activity of TUSC2 + anti–PD-1 treatment was affected by depletion of (A) NK cells and (B) CD8+ T cells, shown in tumor intensity graphs (n = 5 mice/group). C, Ratio of IFNγ (Th1) and IL4 (Th2) serum cytokines determined by Luminex assay. D, Concentration of IL18 and IL15 cytokine in NK cell–depleted and nondepleted mice. Mean ± SD, n = 3. E, Fold expression of IL15Ra and IL18R1 in sorted NK cells from mice treated with TUSC2. Mean ± SD, n = 3. F, NanoString analysis of mRNA expression of IL15Ra and IL18R1 in tumors treated with TUSC2. *, P < 0.05; **, P < 0.01; ***, P < 0.001.

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    Figure 5.

    TUSC2 + anti–PD-1 treatment significantly improved survival in a Kras-mutant lung metastasis model. A, PD-L1 expression determined by flow cytometry in 344SQ-luc and CMT167-luc cells. B, Sequential treatment shown schematically. C, Survival is shown in Kaplan–Meier curves after treatment (n = 10 mice/group). D, Bioluminescence showed lung specific colonization of tumor cells. A representative of 3 independent experiments shown. E, Dissected lung images show tumor nodule status 2 weeks after tumor implantation. (F) NK, (G) Treg, (H) MDSC, and (I) PD-L1+ and PD-L2+ leukocyte infiltration determined by flow cytometry of single cells prepared from metastasized lungs. Data were normalized based on per gram of tumor tissue (23). PD + CT indicate anti–PD-1 + anti–CTLA-4 treatment. Mean ± SD; n = 5. *, P < 0.05; **, P < 0.01; ***, P < 0.001.

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    Figure 6.

    TUSC2 + anti–PD-1 treatment altered expression of immune genes in tumor microenvironment. Gene expression analysis of a NanoString pan-cancer immune panel of 776 genes was performed for 12 samples (n = 3/treatment) from four treatment groups. A, Heat map shows the overall significant genes among treatment groups. B, Pair-wise comparison between TUSC2 + anti–PD-1 and anti–PD-1 statistically significant genes are shown in colors. C, Selected genes known for antitumor immune response were highly upregulated at least 2-fold in the combination treatment. D–F, Fold changes in expression of CD8, IFNγ, and transcription factors Tbx21 and Gata3, respectively.

Additional Files

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    • Supplemental Figure Legends - S1. Gating strategy of peripheral blood leukocytes and splenocytes was shown to determine immune subpopulations for multi-color flow cytometry assay. S2. Effect of NK depletion antibody (NK1.1) on other immune cells. S3. Effect of CD8 T depletion on other immune cells. S4. NanoString gene expression analysis in tumor microenvironment.
    • Supplemental Figures - Supplemental Figures 1-4
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Cancer Immunology Research: 6 (2)
February 2018
Volume 6, Issue 2
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TUSC2 Immunogene Therapy Synergizes with Anti–PD-1 through Enhanced Proliferation and Infiltration of Natural Killer Cells in Syngeneic Kras-Mutant Mouse Lung Cancer Models
Ismail M. Meraz, Mourad Majidi, Xiaobo Cao, Heather Lin, Lerong Li, Jing Wang, Veera Baladandayuthapani, David Rice, Boris Sepesi, Lin Ji and Jack A. Roth
Cancer Immunol Res February 1 2018 (6) (2) 163-177; DOI: 10.1158/2326-6066.CIR-17-0273

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TUSC2 Immunogene Therapy Synergizes with Anti–PD-1 through Enhanced Proliferation and Infiltration of Natural Killer Cells in Syngeneic Kras-Mutant Mouse Lung Cancer Models
Ismail M. Meraz, Mourad Majidi, Xiaobo Cao, Heather Lin, Lerong Li, Jing Wang, Veera Baladandayuthapani, David Rice, Boris Sepesi, Lin Ji and Jack A. Roth
Cancer Immunol Res February 1 2018 (6) (2) 163-177; DOI: 10.1158/2326-6066.CIR-17-0273
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