Document Detail


Adenovirus expressing both thymidine kinase and soluble PD1 enhances antitumor immunity by strengthening CD8 T-cell response.
MedLine Citation:
PMID:  23337984     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-22
Journal Detail:
Title:  Molecular therapy : the journal of the American Society of Gene Therapy     Volume:  21     ISSN:  1525-0024     ISO Abbreviation:  Mol. Ther.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-01     Completed Date:  2013-10-22     Revised Date:  2014-03-06    
Medline Journal Info:
Nlm Unique ID:  100890581     Medline TA:  Mol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  688-95     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adenoviridae / genetics
Animals
Antigens, CD274 / genetics*,  metabolism
Antigens, Neoplasm / genetics,  immunology
Antineoplastic Agents / pharmacology
CD8-Positive T-Lymphocytes / immunology*
Cancer Vaccines / immunology,  therapeutic use*
Cell Line, Tumor
Dendritic Cells / immunology,  metabolism
Female
Genetic Vectors*
Immunity, Cellular / genetics,  immunology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Transgenic
T-Lymphocytes, Cytotoxic / immunology
Telomerase / genetics,  metabolism
Thymidine Kinase / genetics*,  metabolism
Trans-Splicing
Chemical
Reg. No./Substance:
0/Antigens, CD274; 0/Antigens, Neoplasm; 0/Antineoplastic Agents; 0/CD274 protein, human; 0/Cancer Vaccines; EC 2.7.1.21/Thymidine Kinase; EC 2.7.7.49/TERT protein, human; EC 2.7.7.49/Telomerase
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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