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

Direct link
Adenovirus CD40 Ligand Gene Therapy Counteracts Immune Escape Mechanisms in the Tumor Microenvironment
(Gen och immunoterapi gruppen)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology. (Gen och immunoterapi gruppen)
(Gen och immunoterapi gruppen)
(Gen och immunoterapi gruppen)
Show others and affiliations
2004 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 172, no 11, 7200-7205 p.Article in journal (Refereed) Published
Abstract [en]

Tumors exhibit immune escape properties that promote their survival. These properties include modulation of Ag presentation, secretion of immunosuppressive factors, resistance to apoptosis, and induction of immune deviation, e.g., shifting from Th1- to Th2-type responses. These escape mechanisms have proven to hamper several immunotherapeutic strategies, and efforts need to be taken to revert this situation. We have studied the immunological effects of introducing CD40 ligand (CD40L), a potent dendritic cell activation molecule, into the tumor micromilieu by adenoviral gene transfer. For this purpose, a murine bladder cancer model (MB49) was used in C57BL/6 mice. The MB49 cells are known to induce IL-10 in the tumor environment. IL-10 potently inhibits the maturation of dendritic cells and thereby also the activation of CTLs. In this paper we show that CD40L immunogene therapy suppresses IL-10 and TGF-beta production (2-fold decrease) and induces a typical Th1-type response in the tumor area (200-fold increase in IL-12 production). The antitumor responses obtained were MB49 cell specific, and the cytotoxicity of the stimulated CD8(+) cells could be blocked by IL-10. Adenovirus CD40L therapy was capable of regressing small tumors (five of six animals were tumor free) and inhibiting the progression of larger tumors even in the presence of other escape mechanisms, such as apoptosis resistance. Furthermore, CD40L-transduced MB49 cells promoted the maturation of dendritic cells (2-fold increase in IL-12) independently of IL-10. Our results argue for using adenovirus CD40L gene transfer, alone or in combination with other modalities, for the treatment of Th2-dominated tumors.

Place, publisher, year, edition, pages
2004. Vol. 172, no 11, 7200-7205 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-95728PubMedID: 15153545OAI: oai:DiVA.org:uu-95728DiVA: diva2:170052
Available from: 2007-04-12 Created: 2007-04-12 Last updated: 2010-09-13Bibliographically 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


Search in DiVA

By author/editor
Loskog, AngelicaDzojic, HelenaVikman, SofiaEssand, MagnusKorsgren, OlleTötterman, Thomas H.
By organisation
Clinical ImmunologyDepartment of Oncology, Radiology and Clinical Immunology
In the same journal
Journal of Immunology
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 294 hits
ReferencesLink to record
Permanent link

Direct link