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Laboratory for Tumor- and Immune Cell- Metabolism

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Prof. Dr. Marina Kreutz

Internal Medicine III

Molecular Oncology
University Hospital Regensburg
Franz-Josef-Strauss Allee 11
93042 Regensburg, Germany
Tel.: +49 (0)941 944 5587 Fax: +49 (0)941 944 5593
e-mail: marina.kreutz@klinik.uni-regensburg.de

Group members:
(for email please type firstname.lastname@klinik.uni-regensburg.de)

Area of interest I 

Differentiation and activation of immune cells in the tumor microenvironment:  

  • role of tumor-derived lactic acid for the immunomodulation in vitro and in vivo
  • pharmacological targeting of glucose metabolism 

Principal Investigators: Prof. Marina Kreutz, Dr. Katrin Singer, Dr. Gudrun Köhl 


The function of tumor-infiltrating immune cells is depressed and several tumor-derived factors have been implicated as potential mediators including cytokines and lactate. Lactate accumulates in the tumor microenvironment due to the accelerated glycolysis of tumor cells, a phenomenon known as “Warburg effect”. We and others have shown that lactate inhibits both the differentiation of monocytes to dendritic cells and the activation of T cells. In this project we will analyze underlying mechanisms by gene array and proteome analyses. In addition, we investigate the immune modulation by lactic acid in a syngeneic mouse model. For this purpose we have already generated stable murine melanoma cell lines with low lactate secretion by means of LDH-A short hairpin RNA technology. The growth of these tumor cells in immunocompetent C57/Bl6 mice or immunodeficient Rag-/- mice and the tumor immune cell infiltrate will be analyzed. In parallel we will investigate the impact of pharmacological modulation of tumor glycolysis on immune cell function in vivo. Our hypothesis is that inhibition of tumor cell glycolysis not only impairs tumor cell function directly but could also restore the immune response against tumor cells. Glycolysis inhibitors therefore may represent pharmacological agents to support cancer immunotherapies. 

Funded by the DFG KFO 262 

Co-Workers: Almut Brand (M.Sc.), Gabriele Schönhammer (MTA)                                                     


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.


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, 109:3812-3819. 


Dietl K, Renner K, Dettmer K, Timischl B, Eberhart K , Dorn C, Hellerbrand C, Kunz-Schughart L, Oefner P, Andreesen R, Gottfried E, Kreutz M (2010). Tumor-derived lactic acid and acidification inhibit TNF secretion of human monocytes: role of glucose metabolism. J Immunol Feb 1;184(3):1200-9. 


Singer K, Kastenberger M, Gottfried E, Hammerschmied C, Büttner M, Aigner M, Seliger B, Walter B, Schlösser H, Hartmann A, Andreesen R,  Mackensen A and Kreutz M  (2011). Warburg phenotype in renal cell carcinoma: High expression of glucose-transporter 1 (GLUT-1) correlates with low CD8+ T-cell infiltrate in the tumor. Int J Cancer  May 1;128(9):2085-95. 


M Singer K, Gottfried E, Kreutz M, Mackensen A (2011). Suppression of T cell responses by tumor metabolites. Cancer Immunol. Immunother. Mar;60(3):425-31. Review


Mendler AN, Hu B, Prinz PU, Kreutz M, Gottfried E, Noessner E (2012).Tumor lactic acidosis suppresses CTL function by inhibition of p38 and JNK/c-Jun activation. Int J Cancer. Aug 1;131(3):633-40. doi: 10.1002/ijc.26410. 


Gottfried E, Lang SA, Renner K, Bosserhoff A, Gronwald W, Rehli M, Einhell S, Gedig I, Singer K, Seilbeck A, Mackensen A, Grauer O, Hau P, Dettmer K, Andreesen R, Oefner PJ, Kreutz M. (2013) New aspects of an old drug--diclofenac targets MYC and glucose metabolism in tumor cells. PLOS ONE. Jul 9;8(7).


Peter K, Rehli M, Singer K, Renner-Sattler K, Kreutz M. Lactic acid delays the inflammatory response of human monocytes. (2015) Biochem Biophys Res Commun. Feb 13;457(3).


Area of interest II 


Principal Investigators: Prof. Marina Kreutz, Dr. Kathrin Renner

 Immune cells have to be differentiated and activated to guarantee an effective immune response. The basis for immune cell differentiation and activation is an optimal energy supply to support specific cell functions. During activation immune cells undergo changes in their metabolism that are characteristic for a given immune cell population. Different T cell types have distinct metabolic needs and metabolism has a tremendous impact on T cell function, e.g. glucose deprivation inhibits CD8+ T cell function. Similar results have been reported for myeloid cells as dendritic cell differentiation and activation rely on glucose metabolism.

Disturbance of immune cell metabolism can result in immunosuppression. Changes in cell metabolism also accompany tumor/leukemia development. Many solid tumors but also leukemia cells show an accelerated glucose metabolism and the resulting high lactate secretion inhibits immune cell function. 

The aim of this project is to develop strategies selectively affecting tumor cells while preserving T cell function. Therefore a detailed understanding of the relationship between metabolism and immune cell function in the human system is mandatory. Therapeutic intervention in the tumor metabolism can directly target tumor cells and could also rescue the anti-tumor response of immune cells. 

Funded by the RCI 

Funded by the DFG KFO 262  

Co-Workers: bChristina Bruss (M.Sc.), Stephanie Färber (MTA)                                                     


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, 109:3812-3819. 


Dietl K, Renner K, Dettmer K, Timischl B, Eberhart K , Dorn C, Hellerbrand C, Kunz-Schughart L, Oefner P, Andreesen R, Gottfried E, Kreutz M (2010). Tumor-derived lactic acid and acidification inhibit TNF secretion of human monocytes: role of glucose metabolism. J Immunol Feb 1;184(3):1200-9. 


Eberhart K, Renner K, Ritter I, Kastenberger M, Singer K, Hellerbrand C, Kreutz M, Kofler R, Oefner PJ (2009). Low doses of 2-deoxy-glucose sensitize acute lymphoblastic leukemia cells to glucocorticoid-induced apoptosis. Leukemia, Nov;23(11):2167-70.

Schmidl C, Renner K, Eder R, Peter K, Timo Lassmann T, Balwierz PJ, Itoh M, Nago-Sato S, Kawaji H, Carninci P, Suzuki H, Hayashizaki A, Andreesen R, Hume DA, Hoffmann P, Forrest ARR, Kreutz MP, Edinger M, Rehli M,for the FANTOM consortium (2014) Transcription and enhancer profiling in human monocyte subsets Blood  Apr 24;123(17)

Peter K, Rehli M, Singer K, Renner-Sattler K, Kreutz M. Lactic acid delays the inflammatory response of human monocytes.(2015) Biochem Biophys Res Commun. Feb 13;457(3)


Area of interest III

Interplay between NOD2/CARD15 and vitamin D3 for the regulation of alloreactions during stem cell transplantation

Principal Investigators: Prof. Marina Kreutz, Prof. Ernst Holler, Dr. Katrin Peter

 Polymorphisms within the innate immune receptor NOD2/CARD15 and low levels of vitamin D3 are associated with severe graft-versus-host disease (GvHD) after allogeneic stem cell transplantation (SCT). Data from our transplantation unit indicate that SCT patients supplemented with high-dose vitamin D3 do not develop severe GvHD up to day 100. Therefore, the central hypothesis of this project is that variants of NOD2/CARD15 and expression of vitamin D3-metabolizing enzymes and the vitamin D3 serum levels determine the character of the immune response, the T helper cell balance and as a consequence the development of GvHD.

In this project we analyze the impact of Vitamin D3 supplementation and NOD2/CARD15 status on immune cell composition and function in the skin/gut and blood of SCT patients. Furthermore, we investigate the direct effect of NOD ligands in combination with vitamin D3 on the generation of T regulatory cells.

Funded by the DFG KFO 243  

Co-Workers: Carina Matos (M.Sc.), Alice Peuker (MTA) 


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. 

Kreutz, M.; Eissner, G.; Hahn, J.; Andreesen, R.; Drobnik, W.; Holler, E. (2004): Variations in 1 alpha,25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3 serum levels during allogeneic bone marrow transplantation. Bone Marrow Transplant 33 (8), S. 871–873.

Kreutz, Marina; Karrer, Sigrid; Hoffmann, Petra; Gottfried, Eva; Szeimies, Rolf-Markus; Hahn, Joachim et al. (2012): Whole-body UVB irradiation during allogeneic hematopoietic cell transplantation is safe and decreases acute graft-versus-host disease. In: J Invest Dermatol 132 (1), S. 179–187. 

Area of interest IV

Impact of the oncometabolite D-2-hydroxyglutarate (D-2-HG) on immune cells and tumor cells

Principal Investigators: Prof. Marina Kreutz 

Mutations in the genes encoding isocitrate dehydrogenase (IDH) 1 and 2 have been detected in acute myeloid leukemia (AML) blasts of up to 20% of patients and in glioma cells. Cytoplasmic IDH1 and mitochondrial IDH2 are key metabolic enzymes that convert isocitrate to -ketoglutarate (-KG). Cancer associated IDH mutant enzymes induce a neomorphic function to produce the oncometabolute D- 2-HG from -KG. As a result, leukemia cells accumulate large amounts of D-2-HG and several studies have shown increased levels of 2-HG in the serum of AML patients with IDH mutations. D-2-HG is structurally similar to -KG and acts as a competitive inhibitor of -KG-dependent enzymes, including the myeloid tumor suppressor TET2 and JmjC-domain containing histone demethylases. Epigenetic alterations associated with IDH mutations result in changes of gene expression and tumorigenesis.  D-2-HG is also capable of stimulating tumor cell proliferation and suppressing hematopoietic differentiation in cell culture leukemia models. However, effects of 2-HG on differentiation of non-malignant hematopoietic cells are not described so far. In this project we will investigate the effect of 2-HG on human immune cells like dendritic cells (DC) and T cells. Our preliminary data show that 2-HG decreases the secretion of IL-12 in DCs, which possibly impairs T-cell activation. The underlying mechanism of this effect will be analyzed (e.g. transcriptional regulation of cytokine secretion) and we will compare the impact of 2-HG on non-malignant hematopoietic cells and leukemia cells. 

Funded by the DFG KFO 262 

Co-Workers: Monika Wehrstein, Zugey Elizabeth Cardenas Conejo (DAAD fellowship) 


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