Research Activities of the
Laboratory for (Tumor-)Metabolism
and Immune Cell Function

 
Our own findings indicate that the glycolysis end product lactate is found in the sera of tumor patients and inhibits immune cell function. In our laboratory, the interaction of immune cells with tumor cells is investigated in a tumor spheroid model. Spheroids are three dimensional tumor cultures and represent a model for non-vascularized tumor sites and metastases. We could show that different types of tumor spheroids suppress dendritic cell differentiation and T cell activation and identified lactic acid as one factor responsible for the modulation in the tumor environment. Therefore the characteristic energy metabolism of tumor cells leads to immune suppression and contributes to immune escape processes at the tumor site. We are currently characterizing the metabolom of different tumor entities and analyze the effects of tumor metabolites on immune cell function. A metabolic footprint of specific tumors will perhaps allow the identification of patient subsets responsive to immune therapy and modulation of the metabolic activity of tumor cells may increase T cell activation at the tumor site.

Area of Interest II: Vitamin D₃ metabolism and immune cell differentiation
Blood monocytes migrate into the tissue where the specific microenvironment determines their fate, e.g., differentiation into the various types of tissue macrophages or dendritic cells. The active form of vitamin D, 1 alpha ,25-dihydroxyvitamin D₃ ( 1,25 (OH)₂ D₃) is one possible factor which, at least in vitro, can induce the differentiation of macrophages, but inhibits dendritic cell differentiation. It also modulates the activity of B-and T-lymphocytes and seems to be involved in the generation of regulatory T cells.

 
The normal serum level of 1,25 (OH)₂ D₃ is relatively low (~10^-10M), whereas that of 25-hydroxyvitamin D₃ (25(OH)D₃), the major circulating vitamin D metabolite, is about 1000-fold higher. Synthesis of 1,25 (OH)₂ D₃ from its precursor 25(OH)D₃ normally occurs in the kidney, however, we and others have shown that macrophages and dendritic cells can also convert 25(OH)D₃ into 1,25(OH)₂D₃. This production most likely does not exert systemic effects but rather has a local paracrine function. We are interested in the immune regulatory potential of 1,25 (OH)₂ D₃ and could show that low 25 (OH) D₃ and 1,25 (OH)₂ D₃ serum levels are linked to the occurrence of graft versus host disease/GvHD. Currently we investigate   polymorphisms of vitamin D metabolizing enzymes (CYP27A1 and CYP27B1) and their relevance for GvHD.

Funding
The group is supported by: Deutsche Forschungsgemeinschaft (German Research Society), Wilhelm Sander-Stiftung and the Regensburg Research Foundation (ReForM).  

Selected References

• Kreutz, M. and R. Andreesen (1990), Induction of human monocyte into macrophage maturation by 1,25-dihydroxyvitamin D₃. Blood, 76:2457-2461.
• Kreutz, M ., R. Andreesen, S.W. Krause, H. Reichel (1993), 1,25-Dihydroxyvitamin D₃ production and vitamin D receptor expression are developmentally regulated during in vitro differentiation of human monocytes into macrophages. Blood, 82:1300-1307
• Konur, A., M. Kreutz, S.W. Krause, R. Knüchel, R. Andreesen, (1996), Three-dimensional co-culture of human monocytes and macrophages with tumor cells: Analysis of macrophage differentiation and activation, Int. J. Cancer, 66:645-652
• Konur, A., S.W. Krause, M. Rehli, M. Kreutz, R..Andreesen, (1996), Human monocytes induce a   carcinoma cell line to secret high amounts of nitrite oxide, J..Immunol., 157:2109-2115
• Konur, A., M. Kreutz, R. Knüchel, S.W. Krause, R. Andreesen (1998), Cytokine repertoire during maturation of monocytes to macrophages within spheroids of malignant and non-malignant urothelial cell lines, Int. J. Cancer, 78:648-653
• Fritsche, J., M. Moser, S. Faust, A. Peuker, R. Büttner, R. Andreesen, M. Kreutz (2000), Molecular cloning and characterization of a human metalloprotease disintegrin-a novel marker for dendritic cell differentiation, Blood 96:732-739
• Silzle T, Kreutz M, Dobler MA, Brockhoff G, Knuechel R, Kunz-Schughart LA (2003),Tumor-associated fibroblasts recruit blood monocytes into tumor tissue, Eur J mmunol.,33(5):1311-20.
• Fritsche J, Mondal K, Ehrnsperger A, Andreesen R, Kreutz M (2003), Regulation of 25-hydroxyvitamin D3-1 a -hydroxylase and production of 1a,25-dihydroxyvitamin D3 by human dendritic cells. Blood. 102:3314-3316
• Kreutz M , Eissner G, Hahn J, Andreesen R, Drobnik W, Holler E (2004).Variations in 1alpha,25-dihydroxyvitamin D(3) and 25-hydroxyvitamin D(3) serum levels during allogeneic bone marrow transplantation. Bone Marrow Transplant., 33:871-873
• Gottfried E., Kunz-Schughart L., Ebner S , Mueller-Klieser W , Hoves S , Andreesen R , Mackensen A , Kreutz M (2006). Tumor-derived lactic acid modulates dendritic cell activation and antigen expression. Blood, 107:2013-2021.
• Gottfried E, Rehli M., Hahn J., Holler E., Andreesen R, Kreutz M. (2006) Monocyte-derived cells express CYP27A1 and convert vitamin D3 into its active metabolite. Biochem. Biophys. Res. Commun., 349:209-213
• Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M, Gottfried E, Schwartz S, Rothe G, Hoves S, Renner K, Timischl B, Mackensen A, Kunz-Schughart L, Andreesen R, Krause SW, Kreutz M (2007) Inhibitory effect of tumor cell derived lactic acid on human T cells. Blood Jan 25; [Epub ahead of print]