| Adenovirus Expressing Both Thymidine Kinase and Soluble PD1 Enhances Antitumor Immunity by Strengthening CD8 T-cell Response. | |
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MedLine Citation:
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PMID: 23337984 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Adenoviruses harboring the herpes simplex virus thymidine kinase (HSVtk) gene under the regulation of a trans-splicing ribozyme targeting human telomerase reverse transcriptase (hTERT-TR) show marked and specific antitumor activity. In addition to inducing tumor cell death by direct cytotoxicity, it is becoming clear that HSVtk also induces antitumor immunity. Programmed death ligand 1 (PD-L1) expressed on tumor cell surfaces mediates tumor-induced immunoresistance by inhibiting PD1-expressing tumor-infiltrating T cells. Here, we explored whether a soluble form of PD1 (sPD1-Ig), which blocks PD-L1, could synergize with TERT-TR-regulated HSVtk to enhance the adenoviral therapeutic efficacy by boosting antitumor immunity. Tumor antigen released by HSVtk-transduced tumors successfully primed tumor antigen-specific CD8 T cells via dendritic cells (DC). Regression of murine tumors was markedly enhanced when sPD1-Ig was incorporated into the adenovirus as compared with a single-module adenovirus expressing only HSVtk. This effect was abolished by CD8 T-cell depletion. Consistent with this, following adoptive transfer of tumor antigen-specific CD8 T cells into tumor-bearing Rag1(-/-) mice, dual-module adenovirus significantly enhanced CD8 T cell-mediated tumor rejection. In addition, secondary tumor challenge at a distal site was completely suppressed in mice treated with a dual-module adenovirus. These results suggest that a dual-targeting strategy to elicit both tumor antigen priming and tumor-induced immunoresistance enhances CD8 T cell-mediated antitumor immunity.Molecular Therapy (2013); doi:10.1038/mt.2012.252. |
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Authors:
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Seung-Pil Shin; Hye-Hyun Seo; Jae-Hun Shin; Hyung-Bae Park; Dong-Pyo Lim; Hyeon-Seok Eom; Yong-Soo Bae; In-Hoo Kim; Kyungho Choi; Sang-Jin Lee |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2013-1-22 |
Journal Detail:
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Title: Molecular therapy : the journal of the American Society of Gene Therapy Volume: - ISSN: 1525-0024 ISO Abbreviation: Mol. Ther. Publication Date: 2013 Jan |
Date Detail:
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Created Date: 2013-1-22 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 100890581 Medline TA: Mol Ther Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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1] Genitourinary Cancer Branch, Research Institute National Cancer Center, Gyeonggi-do, Korea [2] Department of Life Science, Sungkyunkwan University, Suwon, Korea. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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