Improving PD-1 blockade plus chemotherapy for complete remission of lung cancer by nanoPDLIM2
- UPMC Hillman Cancer Center, Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, United States
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, United States
- Norris Comprehensive Cancer Center, Hastings Center for Pulmonary Research, Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, United States
- Department of Medicine, University of Southern California Keck School of Medicine, United States
Figures
Figure 1 with 1 supplement
PDLIM2 repression in human lung cancer involves both epigenetic alteration and genetic deletion, and Pdlim2 genetic deletion in mice leads to development of spontaneous tumors, majorly lung tumors.
(A) TCGA data showing PDLIM2 repression in over 90% of lung tumors if using 50% of the expression level in normal lung tissues as the cut-off (NL, n=110; Tumor, n=1019). (B) TCGA data showing PDLIM2 …
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Figure 1—source data 1
Excel file for the data shown in Figure 1A-G.
- https://cdn.elifesciences.org/articles/89638/elife-89638-fig1-data1-v1.zip
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Figure 1—source data 2
Original files for the DNA gel images shown in Figure 1E.
- https://cdn.elifesciences.org/articles/89638/elife-89638-fig1-data2-v1.zip
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Figure 1—source data 3
PDF file for the DNA gel images shown in Figure 1E with the relevant bands clearly labelled.
- https://cdn.elifesciences.org/articles/89638/elife-89638-fig1-data3-v1.zip
Figure 1—figure supplement 1
Mice with PDLIM2 deletion develop spontaneous tumors, majorly lung tumors.
(A) IHC assays showing decreased and complete loss of PDLIM2 protein expression in the lungs of PDLIM2+/- and PDLIM2-/- mice, respectively. Scale bar, 20 µm. (B) H&E staining of the lung tissues …
Figure 2
Systemic administration of PDLIM2 plasmid nanoparticles shows efficacy in mouse model of refractory lung cancer.
(A) Schedule of lung cancer induction and treatment. (B) Urethane model showing efficacy of intravenous administration of PDLIM2-expression plasmid nanoparticles for refractory lung cancer (n≥6). …
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Figure 2—source data 1
Excel file for the data shown in Figure 2B-E.
- https://cdn.elifesciences.org/articles/89638/elife-89638-fig2-data1-v1.zip
Figure 3
PDLIM2 nanotherapy shows high tumor specificity and low toxicity.
(A) IHC staining showing high PDLIM2 re-expression in lung tumors after PDLIM2 nanotherapy. (B) PCR and IB assays showing lung tumor-specific plasmids delivery and PDLIM2 expression by PDLIM2 …
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Figure 3—source data 1
Excel file for the data shown in Figure 3B, D.
- https://cdn.elifesciences.org/articles/89638/elife-89638-fig3-data1-v1.zip
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Figure 3—source data 2
Original files for the Western blot images shown in Figure 3B.
- https://cdn.elifesciences.org/articles/89638/elife-89638-fig3-data2-v1.zip
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Figure 3—source data 3
PDF file for the Western blot images shown in Figure 3B with the relevant bands clearly labelled.
- https://cdn.elifesciences.org/articles/89638/elife-89638-fig3-data3-v1.zip
Figure 4
PDLIM2 nanotherapy renders lung cancers more vulnerable to chemotherapy.
(A) Urethane model showing synergy of PDLIM2 nanotherapy and chemotherapy in lung cancer treatment (n≥5). (B) IHC staining showing increased lung tumor cell apoptosis by PDLIM2 nanotherapy, …
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Figure 4—source data 1
Excel file for the data shown in Figure 4A-D.
- https://cdn.elifesciences.org/articles/89638/elife-89638-fig4-data1-v1.zip
Figure 5
PDLIM2 nanotherapy increases the efficacy of PD-1 blockade immunotherapy for refractory lung cancer.
(A) IHC staining showing increased TILs in lung tumors by PDLIM2 nanotherapy (n=6). (B) FACS showing increased MHC-I expression in lung tumor cells by PDLIM2 nanotherapy (n=4). (C) Urethane model …
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Figure 5—source data 1
Excel file for the data shown in Figure 5A-F.
- https://cdn.elifesciences.org/articles/89638/elife-89638-fig5-data1-v1.zip
Figure 6 with 3 supplements
Combination of PDLIM2 nanotherapy, chemotherapy and immunotherapy shows great efficacy in lung cancer treatment.
(A) IHC staining showing PD-L1 induction by chemotherapy but not PDLIM2 nanotherapy. (B) Schedule of lung cancer induction and treatment. (C) Urethane model showing high resistance of lung tumors to …
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Figure 6—source data 1
Excel file for the data shown in Figure 6C-H.
- https://cdn.elifesciences.org/articles/89638/elife-89638-fig6-data1-v1.zip
Figure 6—figure supplement 1
PDLIM2 nanotherapy causes no obvious toxicity in major organs.
(H & E) staining showing comparable toxicity in lung, liver, kidney, and spleen between Vec and PDLIM2 group in the context of combinational chemotherapy and PD-1 blockade immunotherapy (n=5). Scale …
Figure 6—figure supplement 2
Epigenetic drugs cause body weight loss in mice with lung cancer.
Mice were i.p. injected with urethane (1 g/kg) for 6 weeks to induce lung tumors, and then treated for 6 weeks with 5-aza-dC and MS-275 (Epi, i.p., 1 mg/kg each, twice per week), carboplatin and …
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Figure 6—figure supplement 2—source data 1
Excel file for the data shown in Figure 6—figure supplement 2.
- https://cdn.elifesciences.org/articles/89638/elife-89638-fig6-figsupp2-data1-v1.zip
Figure 6—figure supplement 3
Epigenetic drugs show better efficacy in lung cancer treatment.
Mice were i.p. injected with urethane (1 g/kg) for 6 weeks to induce lung tumors, and then treated with 5-aza-dC and MS-275 (Epi, i.p., 1 mg/kg each, twice per week), carboplatin and paclitaxel …
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Figure 6—figure supplement 3—source data 1
Excel file for the data shown in Figure 6—figure supplement 3.
- https://cdn.elifesciences.org/articles/89638/elife-89638-fig6-figsupp3-data1-v1.zip
Tables
Key resources table
| Reagent type (species) or resource | Designation | Source or reference | Identifiers | Additional information |
|---|---|---|---|---|
| Gene (Homo sapiens) | PDLIM2 | GenBank | 64236 | |
| Gene (Mus musculus) | Pdlim2 | GenBank | 213019 | |
| Strain, strain background (Mus musculus) | FVB/N | Ref# 6, 28 | Pdlim2flx/flx/SP-C-rtTAtg/−/(tetO)7CMV-Cretg/tg (ΔSPC) | |
| Strain, strain background (Mus musculus) | BAB/c | Ref# 6, 19, 21, 22 | Pdlim2-/- | |
| Commercial assay or kit | in vivo-jetPEI | Polyplus Transfection | 101000030 | |
| Recombinant DNA reagent | pCMV-myc-Pdlim2 | This paper | PDLIM2 plasmid | PDLIM2 expression plasmid |
| Chemical compound, drug | Carboplatin | AdipoGen | AG-CR1-3591 | |
| Chemical compound, drug | Paclitaxel | AdipoGen | AG-CN2-0045 | |
| Cell line (Homo sapiens) | Lung cancer cell lines | Ref# 6 | Calu-6 (RRID:CVCL_0236) H727 (RRID:CVCL_1584) H23 (RRID:CVCL_1547) H358 (RRID:CVCL_1559) SKLU-1 (RRID:CVCL_0629) SW1573 (RRID:CVCL_1720) CALU-1 (RRID:CVCL_0608) 128-88 T (RRID:CVCL_A2AG) H1299 (RRID:CVCL_0060) 273T (RRID:CVCL_Y296) HCC827 (RRID:CVCL_2063) H1650 (RRID:CVCL_1483) H3255 (RRID:CVCL_6831) 343T (RRID:CVCL_A2AK) Calu-3 (RRID:CVCL_0609) H1435 (RRID:CVCL_1470) H1793 (RRID:CVCL_1496) H596 (RRID:CVCL_1571) H838 (RRID:CVCL_1594) H1838 (RRID:CVCL_1594) A-549 (RRID:CVCL_0023) H1975 (RRID:CVCL_1511) | Cell lines maintained in the laboratories of Dr. Gutian Xiao and Dr Zhaoxia Qu |
| Cell line (Homo sapiens) | nontumorigenic bronchial epithelial cell line from normal adult | ATCC | NL20 (RRID:, CVCL_3756, ATCC# CRL-2503) | |
| Software | Flow data acquisition and analysis | BD Biosciences | Accuri C6 | |
| Software | Flow data acquisition | BD Biosciences | FACSDiva | |
| Software | Flow data analysis | FlowJo | FlowJo | |
| Software | Data statistical analysis and graph presentation | GraphPad | Graphpad Prism |
Additional files
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MDAR checklist
- https://cdn.elifesciences.org/articles/89638/elife-89638-mdarchecklist1-v1.docx
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Supplementary file 1
Antibodies and primers used.
- https://cdn.elifesciences.org/articles/89638/elife-89638-supp1-v1.docx
