Impact of drugs targeting tumor metabolism on human CD8 T cell effector functions
Final Report Abstract
Our results clearly demonstrate that T cell effector functions can be preserved in the presence of metabolic inhibitors. Proliferation turned out to be more sensitive, however, even under administration of potent glycolytic inhibitors only a reduction was observed but not a complete blockade. The administration of diclofenac or lumiracoxib, blocking MCT1 and MCT4 and at the same time COX activity, thereby reducing the secretion of the immunosuppressive metabolite prostaglandine E2, turned out to be a promising strategy in the context of immunotherapeutic approaches, underlined by our first in vivo mouse experiments. With regard to glutamine metabolism, there seems to be a window for certain pathway inhibitors, whereas the application of glutamine analogues or pan-glutamine inhibitors most likely results in severe immunosuppression. Further evaluation is warranted to exclude adverse side effects. From the results obtained in this project we conclude, that the detailed analysis of the link between metabolism and CD8+ T cell function and the impact of anti-metabolic drugs reveal possible favourable combinations of anti-metabolic drugs and immunotherapeutic approaches (such as checkpoint inhibitors), which appear to strengthen the anti-tumor immune response and should be tested within clinical trials.
Publications
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(2014) Immunologic and metabolic characteristics of HPV-negative and HPV-positive head and neck squamous cell carcinomas are strikingly different. Virchows Arch. Sep;465(3):299-312
Krupar R, Robold K, Gaag D, Spanier G, Kreutz M, Renner K, Hellerbrand C, Hofstaedter F, Bosserhoff AK
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(2015) Metabolic plasticity of human T cells: Preserved cytokine production under glucose deprivation or mitochondrial restriction, but 2-deoxyglucose affects effector functions. Eur J Immunol. Sep;45(9):2504-16
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
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(2016) LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells, Cell Metabolism Nov 8;24(5):657-671
Brand A., Singer K, Koehl G.E., 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., Herr W., Walenta S., Geissler EK., Pouyssegur J., Villunger A., Steven A., Seliger B., Schreml S., Haferkamp S., Kohl E., Karrer S., Berneburg M., Mueller-Klieser M., Renner K., Kreutz M.
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(2017) Stattic and metformin inhibit brain tumor initiating cells by reducing STAT3-phosphorylation.Oncotarget Jan 31;8(5):8250-8263
Leidgens V, Proske J, Rauer L, Moeckel S, Renner K, Bogdahn U, Riemenschneider JM, Proescholdt M, Vollmann-Zwerenz A, Hau P and Seliger C
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(2018) Combined metabolic targeting with metformin and the NSAIDs diflunisal and diclofenac induces apoptosis in acute myeloid leukemia cells. Frontiers in Pharmacology Nov 2;9:1258
Renner K., Seilbeck A., Kauer N., Ugele I., Siska P.J., Brummer C., Bruss C., Decking S., Fante M., Schmid A., Hammon K., Singer K., Klobuch S., Thomas S., Gottfried E., Peter K., Kreutz M.
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(2018) Combined Modulation of Tumor Metabolism by Metformin and Diclofenac in Glioma. Int J Mol Sci. Aug 31;19(9)
Gerthofer V, Kreutz M, Renner K, Jachnik B, Dettmer K, Oefner P, Riemenschneider MJ, Proescholdt M, Vollmann-Zwerenz A, Hau P, Seliger C
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(2018) D-2-hydroxyglutarate interferes with HIF-1α stability skewing T-cell metabolism towards oxidative phosphorylation and impairing Th17 polarization. Oncoimmunology 7(7):e1445454
Böttcher M, Renner K, Berger R, Mentz K, Thomas S, Cardenas-Conejo ZE, Dettmer K, Oefner PJ, Mackensen A, Kreutz M, Mougiakakos D
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(2018) Double genetic disruption of lactate dehydrogenases A and B is required to ablate the "Warburg effect" restricting tumor growth to oxidative metabolism. J BiolChem. Oct 12;293(41):15947-15961
Ždralević M, Brand A, Di Ianni L, Dettmer K, Reinders J, Singer K, Peter K, Schnell A, Bruss C, Decking SM, Koehl G, Felipe-Abrio B, Durivault J, Bayer P, Evangelista M, O'Brien T, Oefner PJ, Renner K, Pouysségur J, Kreutz M
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(2018) Metabolic targeting synergizes with MAPK inhibition and delays drug resistance in melanoma., Cancer Lett. Nov 24; 442:453-463
Brummer C, Faerber S, Bruss C, Blank C, Lacroix R, Haferkamp S, Herr W, Kreutz M, Renner K
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(2018) Tumor immunoevasion via acidosis dependent induction of regulatory tumor-associated macrophages. Nature Immunology Dec;19(12):1319-1329
Bohn T., Rapp S., Luther N., Klein M., Bruehl T., Kojima N Lopez P:A., Hahlbrock J., Muth S., Endo S., Pektor S., Brand A., Renner K., Popp V., Gerlach K., Vogel D., Lueckel C., Arnold-Schild D., Pouyssegur J., Kreutz M., Huber M., Koenig J., Weigmann B., Probst H., Stebut E., Becker C., Schild H., Schmitt E., Bopp T.
