The research focus of our group is to investigate mechanisms that drive immune regulation mediated by ex vivo generated and tumor resident dendritic cells.
The Laboratory for Tumor Immunology is investigating mechanisms of anti-tumor immunity and resistance against cancer cells, and possibilities of manipulating the immune system with a view to applying results directly to cancer therapy. Our basic research program addresses questions of dendritic cell (DC)-mediated immune regulation in the tumor microenvironment and after pathogen encounter that may cause auto-immunity. In the absence of any threat from microorganisms, DCs maintain a tolerogenic default status or even suppress immune activation. When DCs encounter a microbial infection, they adopt immune stimulatory properties. We found that this ability lasts for only about one day and is subsequently followed by a switch to immune suppression, which is maintained by anti-inflammatory cytokines and immune suppressive effector molecules. Such DC subsets might play a pivotal role in tumor escape from immune surveillance. Thus, the research focus of our group is to investigate mechanisms that drive immune regulation mediated by ex vivo generated and tumor resident DCs.
In our investigations we apply genomics technologies in order to identify molecules in DCs, the blockade of which results in improved immune stimulation indicated by enhanced proliferation of T-lymphocytes. Promising candidate genes are involved in MAPK, JAK/STAT or G-Protein signaling and play a key role in DC-mediated immune regulation. In addition, we identified one metabolic enzyme as a putative effector molecule that causes DC-mediated immune suppression by the release of adenosine-like molecules. Targeting these immune regulatory mechanisms in the tumor microenvironment might be an attractive strategy to improve anti-tumor immunity. For that purpose, we have also started developing polymer particles that may carry pathogenic molecular patterns or small molecule inhibitors to target tumor resident DCs.
Promising observations on the MAPKAPK2 gene in mouse tumor models.
We found mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2) to be a central signaling modulator, which maintains an immune regulatory phenotype in DCs. DCs in which the MAPKAPK2 gene has been deleted strongly support cell-mediated and interleukine 17 dependent immunity in vitro. In this context cytotoxic T-cells primed with antigen-charged DCs from MAPKAPK2 deficient mice have a more than hundred-fold stronger proliferative capacity as compared to co-cultivation with DCs that have an intact MAPKAPK2 gene. Additional evidence for the importance of this gene in DC-mediated immune regulation was derived from in vivo experiments, which showed enhanced tumor growth control and auto-immune encephalitis when MAPKAPK2 was down modulated in DCs. MAPKAPK2 inhibitors to ex vivo manipulate human DCs for clinical intervention are currently under investigation in our lab.
Clinical pilot studies with sarcoma and brain tumor patients.
Early stage clinical trials, including 28 sarcoma patients who received tumor antigen-charged, lipopolysaccharide activated DCs were conducted between 2000 and 2004. Long-term data (5 to 10 years) are currently analyzed.
In cooperation with our partner Activartis Biotech GmbH, a biotech spin off company of the CCRI, a randomized phase II clinical trial for the treatment of patients suffering from an aggressive brain cancer, Glioblastoma Multiforme, is currently being conducted. While one half of the patients receive the current standard treatment, the other half is treated with the DC cancer vaccine in addition to the standard treatment. In May 2013 the inclusion of 78 patients was completed and patients are currently followed for the clinical course of the disease.
With regard to the clinical application of in vitro manipulated DCs, one particular challenge is the identification of biomarkers that may predict the clinical outcome of patients treated with DC-based therapies. To address this problem, we investigate the T-cell receptor repertoire as a surrogate for T-cell antigen specificity using next generation sequencing technologies in patient material and tissues from appropriate mouse models.
Soukup K, Halfmann A, Le Bras M, Sahin E, Vittori S, Poyer F, Schuh C, Luger R, Niederreiter B, Haider T, Stoiber D, Blüml S, Schabbauer G, Kotlyarov A, Gaestel M, Felzmann T, Dohnal AM. (2015) The MAPK-Activated Kinase MK2 Attenuates Dendritic Cell-Mediated Th1 Differentiation and Autoimmune Encephalomyelitis. J Immunol. 15;195(2):541-52.
- Luger R, Valookaran S, Knapp N, Vizzardelli C, Dohnal AM, and Felzmann T. (2013) Toll-like receptor 4 engagement drives differentiation of human and murine dendritic cells from a pro- into an anti-inflammatory mode. PloS one 8:e54879.
Dohnal AM, Luger R, Paul P, Fuchs D, and Felzmann T. (2009) CD40 ligation restores type 1 polarizing capacity in TLR4-activated dendritic cells that have ceased interleukin-12 expression. J Cell Mol Med 13:1741-1750.
Dohnal AM, Graffi S, Witt V, Eichstill C, Wagner D, Ul-Haq S, Wimmer D, and Felzmann T. (2009) Comparative evaluation of techniques for the manufacturing of dendritic cell-based cancer vaccines. J Cell Mol Med 13:125-135.
Dohnal AM, Witt V, Hugel H, Holter W, Gadner H, and Felzmann T. (2007) Phase I study of tumor Ag-loaded IL-12 secreting semi-mature DC for the treatment of pediatric cancer. Cytotherapy 9:755-770.
Hüttner KG, Breuer SK, Paul P, Majdic O, Heitger A, and Felzmann T. (2005) Generation of potent anti-tumor immunity in mice by interleukin-12-secreting dendritic cells. Cancer Immunol Immunother 54:67-77.