III-3. Immunometabolomics|Prof. Dr. Marina Kreutz

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. Similar results have been reported for myeloid cells as dendritic cell differentiation and activation relies on glucose metabolism.

Disturbance of immune cell metabolism can result in immunosuppression and glucose deprivation inhibits CD8+ T cell function. 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.

Publications

  • Gottfried E, Kunz-Schughart LA, 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, Mar 1;107(5):2013-21.
  • 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.
  • Chirasani SR, Leukel P, Gottfried E, Hochrein J, Stadler K, Neumann B, Oefner PJ, Gronwald W, Bogdahn U, Hau P, Kreutz M*, Grauer OM* (2013). Diclofenac inhibits lactate formation and efficiently counteracts local immune suppression in a murine glioma model. Int J Cancer. Feb 15;132(4):843-53. *M.K. and O.M.G. contributed equally to this work.
  • 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. 2013 Jul 9;8(7).
  • Renner K, Geiselhöringer AL, Fante M, Bruss C, Färber S, Schönhammer G, Peter K, Singer K, Andreesen R, Hoffmann P, Oefner P, Herr W, Kreutz M (2015). Metabolic plasticity of human T cells: Preserved cytokine production under glucose deprivation or mitochondrial restriction, but 2-deoxy-glucose affects effector functions. Eur J Immunol. Sep;45(9):2504-16.
  • Henrich FC, Singer K, Poller K, Bernhardt L, Strobl CD, Limm K, Ritter AP, Gottfried E, Völkl S, Jacobs B, Peter K, Mougiakakos D, Dettmer K, Oefner PJ, Bosserhoff AK, Kreutz MP, Aigner M, Mackensen A.(2016). Suppressive effects of tumor cell-derived 5'-deoxy-5'-methylthioadenosine on human T cells. Oncoimmunology. Jun 10;5(8):e1184802. doi: 10.1080/2162402X.2016.1184802. eCollection 2016 Aug
  • Brand A, Singer K, Koehl GE, Kolitzus M, Schoenhammer G, Thiel A, Matos C, Bruss C, Klobuch S, Peter K, Kastenberger M, Bogdan C, Schleicher U, Mackensen A, Ullrich E, Fichtner-Feigl S, Kesselring R, Mack M, Ritter U, Schmid M, Blank C, Dettmer K, Oefner PJ, Hoffmann P, Walenta S, Geissler EK, Pouyssegur J, Villunger A, Steven A, Seliger B, Schreml S, Haferkamp S, Kohl E, Karrer S, Berneburg M, Herr W, Mueller-Klieser W, Renner K, Kreutz M. (2016) LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells. Cell Metab. Nov 8;24(5):657-671
  • Renner K, Singer K, Koehl GE, Geissler EK, Peter K, Siska PJ, Kreutz M.(2017). Metabolic Hallmarks of Tumor and Immune Cells in the Tumor Microenvironment. Front Immunol. Mar 8;8:248. doi: 10.3389/fimmu.2017.00248. eCollection 2017. Review
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