These days immunotherapies with checkpoint inhibitors and CAR T cells play a vital role in the treatment of cancer patients. That said, a variety of mechanisms by which solid tumors escape the immune system limit their therapeutic efficacy—with the metabolic tumor environment increasingly being attributed to T-cell therapy failure.

The Kreutz group is a pioneer in the field of immunometabolism, and was among the first to demonstrate T-cell immunosuppression triggered by lactic acid in the tumor micro environment. This occurs due to an accelerated tumor glucose metabolism known as the “immunological Warburg effect.” Additional research by the Immunometabolomics Clinical Cooperation Group has gone on to show a negative correlation between a high glycolytic index in melanoma patients’ biopsies and their response to checkpoint inhibition. Findings have shown that the genetic knockout of the lactate-producing enzyme leads to an increased response to checkpoint blockade in a murine melanoma model. A screen for drugs that stabilize T-cell function in this acidic environment reveals that the nonsteroidal anti-inflammatory drug ‘diclofenac’ inhibits lactate secretion and acidification—augmenting the response to checkpoint inhibition.

Based on these data a clinical trial has been initiated together with the Universities of Mainz and Essen. In this trial 'diclofenac' will be used to support checkpoint therapy (funding is focused on Translational Oncology provided by the German Cancer Aid [DKH]). Professor Marina Kreutz holds a patent (EP3104863) for the use of salicylates in the treatment of cancer and has filed a patent (DE102015103618) for the application of 'diclofenac' in cancer therapy.

In addition to this, the Immunometabolomics Clinical Cooperation Group is seeking to strengthen T cells and their resilience within this acidic tumor environment. In collaboration with the Core Facility (NGS & Data Technologies), RNAseq analyses of lactic acid-resistant T cells brought up interesting target genes. Together with Professor Simone Thomas (T-Cell Therapy Group) and Professor Hinrich Abken (Research Division Genetic Immunotherapy) and Professor Luca Gattinoni (Research Division Functional Immune Cell Modulation) they plan to equip T cells with additional genes to strengthen and support their efficacy in immunotherapeutic application.

Currently, Professor Kreutz is collaborating with Dr. Chi Van Dang (Ludwig Institute for Cancer Research, New York, USA) in order to deepen her investigations into metabolic targeting. Another ongoing collaboration with Merck KGaA, (Darmstadt, Germany) aims to further explore the impact of MCT inhibitors in the tumor environment.

Discover more by visiting Professor Kreutz’ dedicated UKR page!

Here is a selection of the most important publications from the last few years:

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. Inhibitory effect of tumor cell derived lactic acid on human T cells. Blood. 2007. doi: 10.1182/blood-2006-07-035972. (1726 citations)

Gottfried E, Kunz-Schughart L, Ebner S, Mueller-Klieser W, Hoves S, Andreesen R, Mackensen A, Kreutz M. Tumor-derived lactic acid modulates dendritic cell activation and antigen expression. Blood. 2006. doi: 10.1182/blood-2005-05-1795. (644 citations)

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. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. 2016. doi: 10.1016/j.cmet.2016.08.011. (1173 citation)

Comment in : Cell Metab. 2016 Nov 8;24(5):649-650. doi: 10.1016/j.cmet.2016.10.015, Lactate Wreaks Havoc on Tumor-Infiltrating T and NK Cells by Scott KE, Cleveland JL.

Comment in: Nat Rev Immunol 2016 Oct 26;16(11):658-659. doi: 10.1038/nri.2016.119, Tumour immunology: Suppressive metabolites by Anna Dart

Renner K, Bruss C, Schnell A, Koehl G, Becker H, Fante M, Menevse AN, Kauer N, Blazquez R, Hacker L, Decking SM, Bohn T, Faerber S, Evert K, Aigle L, Amslinger S, Landa M, Krijgsman O, Rozeman EA, Brummer C, Siska PJ, Singer K, Pektor S, Miederer M, Peter K, Gottfried E, Herr W, Marchiq I, Pouyssegur J, Roush WR, Ong S, Warren S, Pukrop T, Beckhove P, Lang SA, Bopp T, Blank CU, Cleveland JL, Oefner PJ, Dettmer K, Selby M, Kreutz M. Restricting Glycolysis Preserves T Cell Effector Functions and Augments Checkpoint Therapy. Cell Rep. 2019. doi: 10.1016/j.celrep.2019.08.068. (194 citations)

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. Double genetic disruption of lactate dehydrogenases A and B is required to ablate the “Warburg effect” restricting tumor growth to oxidative metabolism. J BiolChem. 2018 Oct 12;293(41):15947-15961. (165 citations)

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). (105 citations)

Prof. Dr. Marina Kreutz

Head of LIT Cooperation Group | Immunometabolomics

Tel: +49 941 944–38480
Email: Marina.Kreutz@ukr.de

Research team

Prof. Marina Kreutz

Head of LIT Cooperation Group | Immunometabolomics

Dr. Nathalie Babl

Postdoctoral Scientist

Dr. Carina Saraiva de Matos

Postdoctoral Scientist

Florian Voll

PhD Student