Differentiation and activation of immune cells in the tumor microenvironment: role of tumor-derived lactate in immunomodulation in vitro and in vivo

• Applicants: Dr. Elisabeth Kohl; Professorin Dr. Marina P. Kreutz; Dr. Gudrun Köhl
• Subject Area: Hematology, Oncology
• Term: from 2011 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 190230491

• Final Report Year: 2019

Final Report Abstract

The tumor microenvironment modulates the activation of infiltrating cells and thereby regulates the balance between immune response and tolerance. The main findings of this project are that tumorderived lactic acid can suppress T and NK cells in vitro and in vivo which adds another piece to the tumor immune suppression puzzle. Based on these data we speculated that tumor derived lactic acid may limit the efficacy of checkpoint therapy. We demonstrated in several publications that the NSAID diclofenac blocks lactate secretion while preserving T cell effector functions which may result in a better response to checkpoint therapy. Our very recent data support this conclusion as we were able to show that diclofenac can improve checkpoint therapy in a murine breast carcinoma model. And we hope that these data will help us to get funding to confirm our findings in a clinical trial.

Publications

• (2012). Tumor lactic acidosis suppresses CTL function by inhibition of p38 and JNK/c-Jun activation. Int J Cancer. Aug1;131(3):633-40
  Mendler AN, Hu B, Prinz PU, Kreutz M, Gottfried E, Noessner E
  (See online at https://doi.org/10.1002/ijc.26410)
• (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
  Chirasani SR, Leukel P, Gottfried E, Hochrein J, Stadler K, Neumann B, Oefner PJ, Gronwald W, Bogdahn U, Hau P, Kreutz M, Grauer OM
  (See online at https://doi.org/10.1002/ijc.27712)
• (2013). Distinct metabolic differences between various human cancer and primary cells. Electrophoresis. 2013 Jul 16
  Dettmer K, Vogl FC, Ritter AP, Zhu W, Nürnberger N, Kreutz M, Oefner PJ, Gronwald W, Gottfried E
  (See online at https://doi.org/10.1002/elps.201300228)
• (2013). New Aspects of an Old Drug - Diclofenac Targets MYC and Glucose Metabolism in Tumor Cells. PLoS One. 2013 Jul 9;8(7)
  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
  (See online at https://doi.org/10.1371/journal.pone.0066987)
• (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
  (See online at https://doi.org/10.1007/s00428-014-1630-6)
• (2015). Lactic acid delays the inflammatory response of human monocytes. Biochem Biophys Res Commun. Feb 13;457(3):412-8
  Peter K, Rehli M, Singer K, Renner-Sattler K, Kreutz M
  (See online at https://doi.org/10.1016/j.bbrc.2015.01.005)
• (2016) LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells. Cell Metab. Nov 8;24(5):657-671
  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
  (See online at https://doi.org/10.1016/j.cmet.2016.08.011)
• (2016) Metformin inhibits proliferation and migration of glioblastoma cells independently of TGF-β2. Cell Cycle. Jul 2;15(13):1755-66
  Seliger C, Meyer AL, Renner K, Leidgens V, Moeckel S, Jachnik B, Dettmer K, Tischler U, Gerthofer V, Rauer L, Uhl M, Proescholdt M, Bogdahn U, Riemenschneider MJ, Oefner PJ, Kreutz M, Vollmann- Zwerenz A, Hau P
  (See online at https://doi.org/10.1080/15384101.2016.1186316)
• (2016). Suppressive effects of tumor cell-derived 5'-deoxy-5'-methylthioadenosine on human T cells. Oncoimmunology. Jun 10;5(8):e1184802
  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
  (See online at https://doi.org/10.1080/2162402X.2016.1184802)
• (2017). Metabolic Hallmarks of Tumor and Immune Cells in the Tumor Microenvironment. Front Immunol. Mar 8;8:248. Review 2016
  Renner K, Singer K, Koehl GE, Geissler EK, Peter K, Siska PJ, Kreutz M
  (See online at https://doi.org/10.3389/fimmu.2017.00248)
• (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
  (See online at https://doi.org/10.1074/jbc.RA118.004180)
• (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
  (See online at https://doi.org/10.1016/j.canlet.2018.11.018)
• (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
  (See online at https://doi.org/10.3390/ijms19092586)
• (2018). Tumor immunoevasion via acidosis dependent induction of regulatory tumor-associated macrophages. Nat Immunol. 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., KoenigJ., Weigmann B., Probst H., Stebut E., Becker C., Schild H., Schmitt E., Bopp T.
  (See online at https://doi.org/10.1038/s41590-018-0226-8)
• Combined metabolic targeting with metformin and the NSAIDs diflunisal and diclofenac induces apoptosis in acute myeloid leukemia cells. Front Pharmacol. 2018 Nov 2; 9:1258
  Renner K., SeilbeckA., Kauer N., Ugele I., Siska P.J., Brummer C., Bruss C., Decking S., FanteM., Schmid A., Hammon K., Singer K., Klobuch S., Thomas S., Gottfried E., Peter K., Kreutz M.
  (See online at https://doi.org/10.3389/fphar.2018.01258)