uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
AdCD40L gene therapy counteracts T regulatory cells and cures aggressive tumors in an orthotopic bladder cancer model
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
2005 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 11, no 24 Pt 1, 8816-8821 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE: The aim of this study was to develop an immunostimulating gene therapy for the treatment of orthotopic bladder carcinoma by transferring the gene for CD40L into the tumor site. CD40L stimulation of dendritic cells induces interleukin-12 expression that drives Th1 type of immune responses with activation of cytotoxic T cells.

EXPERIMENTAL DESIGN: The gene for murine CD40L was transferred into bladders of tumor-bearing mice using an adenoviral vector construct. To facilitate viral uptake, the bladders were pretreated with Clorpactin. Survival of mice as well as transgene expression and immunologic effect, such as resistance to tumor challenge and presence of T regulatory cells, were monitored.

RESULTS: On viral vector instillation, CD40L expression could be detected by reverse transcription-PCR. As a sign of transgene function, interleukin-12 (IL-12) expression was significantly increased. AdCD40L gene therapy cured 60% of mice with preestablished tumors. The cured mice were completely resistant to subcutaneous challenge with MB49 tumor cells, whereas the growth of a syngeneic irrelevant tumor was unaltered. Furthermore, the mRNA expression level of the T regulatory cell transcription factor Foxp3 was evaluated both in tumor biopsies and lymph nodes. There were no differences within the tumors of the different treatment groups. However, Foxp3 mRNA levels were down-regulated in the lymph nodes of AdCD40L-treated mice. Correspondingly, T cells from AdCD40L-treated mice were not able to inhibit proliferation of naive T cells as opposed to T cells from control-treated, tumor-bearing mice.

CONCLUSIONS: AdCD40L gene therapy evokes Th1 cytokine responses and counteracts T regulatory cell development and/or function.

Place, publisher, year, edition, pages
2005. Vol. 11, no 24 Pt 1, 8816-8821 p.
Keyword [en]
Adenoviridae/genetics, Animals, CD40 Ligand/*genetics, Carcinoma/immunology/*therapy, Disease Models; Animal, Epithelium/pathology, Forkhead Transcription Factors/genetics, Gene Therapy, Genetic Vectors/genetics, Interleukin-12/genetics, Lymph Nodes/chemistry, Mice, RNA; Messenger/analysis/metabolism, T-Lymphocytes; Regulatory/*immunology/metabolism, Transduction; Genetic, Urinary Bladder/pathology, Urinary Bladder Neoplasms/immunology/*therapy
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-25657DOI: 10.1158/1078-0432.CCR-05-1817PubMedID: 16361570OAI: oai:DiVA.org:uu-25657DiVA: diva2:53431
Available from: 2007-02-13 Created: 2007-02-13 Last updated: 2017-12-07Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMedhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=16361570&dopt=Citation

Authority records BETA

Loskog, Angelica S.Fransson, Moa E.Tötterman, Thomas H.

Search in DiVA

By author/editor
Loskog, Angelica S.Fransson, Moa E.Tötterman, Thomas H.
By organisation
Department of Oncology, Radiology and Clinical Immunology
In the same journal
Clinical Cancer Research
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 642 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf