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In vitro activation of cancer patient-derived dendritic cells by tumor cells genetically modified to express CD154
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
2002 (English)In: Cancer Gene Therapy, ISSN 0929-1903, E-ISSN 1476-5500, Vol. 9, no 10, 846-853 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE: Triggering of CD40 on antigen-presenting cells via its ligand CD154 is an important event in the initial phase of an immune response against cancer cells. In this study, we investigated the effects of adenoviral CD154 immunomodulatory gene therapy on the activation of human dendritic cells (DCs) in a well-defined in vitro system.

EXPERIMENTAL DESIGN: Human bladder cancer cell lines and tumor cells from patients with renal cell carcinoma (RCC) were transduced with Ad-CD154 vectors or control vectors. Activation of human in vitro generated DCs after coculture with transduced tumor cells was analyzed. Therapeutic efficacy and cytotoxic T-lymphocyte (CTL) activity were assessed in a subcutaneous (s.c.) murine bladder cancer model.

RESULTS: Human bladder cancer cell lines expressing CD154 showed a decreased growth rate, increased apoptosis, and modulated expression of molecules important for recognition by cytotoxic lymphocytes. Further, CD154-expressing allogeneic bladder tumor cell lines and autologous tumor cells from patients with renal cell cancer induced maturation of DCs and stimulated IFN-gamma production from lymphocytes cocultured with mature DCs. In vivo studies showed that CD154 gene therapy was highly effective in wild-type mice but only minimally effective in nude mice. Consequently, strong tumor-specific CTL activity was detected in mice vaccinated with tumor cells expressing CD154.

CONCLUSIONS: Using tumor cell lines as well as patient-derived material, we could show that tumor cells expressing CD154 efficiently induce maturation and activation of DCs as well as activation of lymphocytes. Our murine in vivo studies demonstrate that lymphocytes contribute to the observed antitumor effect in a s.c. bladder tumor model. These studies should stimulate CD154 gene therapy approaches for the treatment of urologic malignancies.

Place, publisher, year, edition, pages
2002. Vol. 9, no 10, 846-853 p.
Keyword [en]
gene therapy, adenoviral vector, bladder cancer, renal cell carcinoma, CD154, dendritic cell
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-89987PubMedID: 12224026OAI: oai:DiVA.org:uu-89987DiVA: diva2:161978
Available from: 2002-09-19 Created: 2002-09-19 Last updated: 2010-09-15Bibliographically approved
In thesis
1. Immunogene Therapy of Bladder Carcinoma: A Preclinical Study
Open this publication in new window or tab >>Immunogene Therapy of Bladder Carcinoma: A Preclinical Study
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis comprises studies on murine and human models of bladder carcinoma with the aim to develop novel immunogene therapies. On the basis of the results presented in this thesis, a clinical trial is underway.

The potential of activating the immune system to combat cancer has long intrigued immunologists. Research has now been intensified and clinically effective treatments are beginning to materialize. We evaluated the induction of anti-tumor responses by inserting immunomodulating genes into tumor cells with adenovectors. Human biopsies and cell lines were positive for adenovirus attachment receptors, and cell lines were easily transduced. CD40L modified cells efficiently induced maturation of dendritic cell (DC). Phenotypical changes of AdCD40L transduced cells, such as increased apoptotic rate, upregulated MHC-I, Fas and TNFR may further strengthen the anti-tumor response.

CD40L modified murine bladder cancer cells activated systemic immunity upon vaccination and in situ injections of AdCD40L inhibited tumor progression. Cytotoxic assays revealed the presence of cytotoxic T cells (CTLs) in vaccinated mice. Many tumors have developed ways to evade the immune system. Bladder carcinoma is associated with immune escape mechanisms like IL10 production. We demonstrated that immunosuppression by IL10 inhibited CTL function and that IL10 suppression may be reverted by AdCD40L therapy.

In conclusion, AdCD40L therapy induces systemic immunity and inhibits tumor progression in murine models. The immunological mechanisms involve maturation of nearby DCs and CTL induction. AdCD40L therapy is effective despite immune escape mechanisms, e.g. IL10 secretion. The thesis argues for using AdCD40L immunogene therapy as a treatment of bladder carcinoma.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2002. 52 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1180
Keyword
Oncology, Immunotherapy, Gene therapy, Immunogene therapy, CD40L, Bladder carcinoma, Onkologi
National Category
Cancer and Oncology
Research subject
Clinical Immunology
Identifiers
urn:nbn:se:uu:diva-2637 (URN)91-554-5402-X (ISBN)
Public defence
2002-10-11, Rudbecksalen, Uppsala, 13:15
Opponent
Available from: 2002-09-19 Created: 2002-09-19 Last updated: 2010-09-15Bibliographically approved

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Loskog, AngelicaTötterman, Thomas H.

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