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

Direct link
Adenovirus-Mediated CD40 Ligand Therapy Induces Tumor Cell Apoptosis and Systemic Immunity in the TRAMP-C2 Mouse Prostate Cancer Model
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
2006 (English)In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 66, no 8, 831-838 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The interaction between CD40 ligand (CD40L) and CD40 on antigen presenting cells is essential for the initiation of antigen-specific T-cell responses, whereas CD40L stimulation of CD40+ tumor cells can induce cellular apoptosis. We investigated the anti-tumor effects induced by CD40L gene transfer into the mouse prostate adenocarcinoma cell line TRAMP-C2, both in vitro and in vivo.

METHODS: TRAMP-C2 cells were transduced with an adenoviral vector encoding CD40L (AdCD40L). The induced expression of co-stimulatory molecules and cell viability was analyzed. AdCD40L-transduced TRAMP-C2 cells were used in prophylactic vaccination studies, while therapeutic studies were performed using peritumoral injections of AdCD40L.

RESULTS: AdCD40L yielded reduced TRAMP-C2 cell viability and induced apoptosis in vitro. Vaccination with CD40L-expressing TRAMP-C2 cells induced anti-tumor immunity and peritumoral AdCD40L injections induced tumor growth suppression.

CONCLUSIONS: Our observations highlight the therapeutic potential of using AdCD40L as a monotherapy or in combination with conventional chemotherapy or novel therapies (e.g., oncolytic viruses). The use of AdCD40L offers an attractive option for future clinical trials.

Place, publisher, year, edition, pages
2006. Vol. 66, no 8, 831-838 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-95729DOI: 10.1002/pros.20344PubMedID: 16491482OAI: oai:DiVA.org:uu-95729DiVA: diva2:170053
Available from: 2007-04-12 Created: 2007-04-12 Last updated: 2010-09-08Bibliographically approved
In thesis
1. Adenovirus-mediated CD40 Ligand Immunotherapy of Prostate and Bladder Cancer
Open this publication in new window or tab >>Adenovirus-mediated CD40 Ligand Immunotherapy of Prostate and Bladder Cancer
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cancer immunotherapy aims at reversing the immunosuppressive tumor environment and enhancing anti-tumor immunity. This thesis comprises studies on murine models for prostate (TRAMP-C2) and bladder (MB49) cancer with the aim to explore if the introduction of an adenoviral vector expressing CD40 ligand (AdCD40L) can induce anti-tumor immune responses.

We show in subcutaneous mouse models that AdCD40L treatment suppresses tumor growth. Bladder cancer is known to secrete immunosuppressive IL-10 which may inhibit T cell function. We show that introducing AdCD40L into mouse bladder tumors inhibits IL-10 production and reverses immunosuppression. AdCD40L-transduced mouse prostate cancer cells showed caspase activation and reduced cell viability. Vaccination with CD40L-modified prostate cancer cells induces anti-tumor responses and protects mice against rechallenge with native TRAMP-C2 cells. In order to enhance AdCD40L therapy, we explored the possibility of combining it with the histone deacetylase inhibitor FK228, also known as depsipeptide. We show that FK228 upregulates coxsackie and adenovirus receptor expression and thereby enhances adenoviral-mediated CD40L expression in both murine and human prostate cancer cells. Increasing amounts of FK228 or AdCD40L reduces prostate cancer cell viability, while the combined treatment gives at least an additive therapeutic effect. Moreover, we show that AdCD40L transduction of prostate cancer cells induces endogenous CD40 expression and sensitize them for CD40L-mediated therapy.

In order to conduct prostate-specific gene therapy, prostate-specific promoters can be used to drive transgene expression. However, there are no reports on prostate-specific promoters that are transcriptionally active in mouse cells. Here we show that by using the two-step transcription activation system (TSTA), we can enhance the activity of a recombinant human promoter sequence and obtain activity in mouse prostate cancer cells as well. This finding paves the way for future studies of prostate-specific gene therapy in immunocompetent mouse models.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 53 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 248
Medicine, immunotherapy, gene therapy, prostate cancer, bladder cancer, adenoviral vector, CD40 ligand, promoter, PPT, TSTA, depsipeptide FK228, TRAMP-C2, Medicin
urn:nbn:se:uu:diva-7810 (URN)978-91-554-6851-4 (ISBN)
Public defence
2007-05-04, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15
Available from: 2007-04-12 Created: 2007-04-12Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Dzojic, HelenaLoskog, AngelicaTötterman, Thomas H.Essand, Magnus
By organisation
Clinical Immunology
In the same journal
The Prostate
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar

Altmetric score

Total: 358 hits
ReferencesLink to record
Permanent link

Direct link