Prof. Marina P. Kreutz
Internal Medicine III
University Medical School Regensburg
Dr. Gudrun Elisabeth Köhl
Dept of Surgery
University Medical School Regensburg
Dr. Elisabeth Kohl
Department of Dermatology,
University Hospital Regensburg
Differentiation and activation of immune cells in the tumor microenvironment: role of tumor-derived lactate in immunomodulation in vitro and in vivo
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 vitro and high levels of lactate correlate with tumor progression and metastatic spread in vivo.
In the previous funding period we studied tumor growth and immune cell infiltration of LDHA deficient murine melanoma cells in vivo. Tumor growth was different in in immuncompetent C57BL/6, but not in immunodeficient RAG2-/- -mice indicating that T cells play a major role in the immunosuppression by lactate. In line with this finding, tumors with high lactate secretion show significantly lower numbers of functionally active CD8+ T cells but an accumulation of myeloid suppressor cells. Furthermore, the impact of pharmacological modulation of glycolysis on immune cell infiltration and activation was investigated in murine tumor models. In a glioma model we demonstrated that diclofenac treatment diminshed intratumoral lactate levels and delayed glioma growth. Similar results were obtained in a murine melanoma model. This new Cox-independent off-target effect of diclofenac was further analyzed in vitro. Here, we could show that diclofenac inhibited Myc expression and decreased glucose uptake and lactate release. Based on these data, we started a clinical trial in patients with actinic keratosis to study the impact of diclofenac (solaraze) on glucose metabolism. Furthermore, we will use clinically applicable drugs that target the tumor metabolism and analyze the resulting tumor growth and immune cell infiltration in murine tumor models. MCT inhibitors (blocking lactate transport) and/or NaHCO3 and proton pump inhibitors (buffering the tumor milieu) in combination with low dose chemotherapy will be applied. Our aim is to provide a rationale for a clinical phase I study in cancer patients with anti-metabolic therapy that targets tumor glucose metabolism and thereby rescues immune cell function.
1. Gottfried, E., L. A. Kunz-Schughart, S. Ebner, W. Mueller-Klieser, S. Hoves, R. Andreesen, A. Mackensen, M. Kreutz. 2006. Tumor-derived lactic acid modulates dendritic cell activation and antigen expression. Blood 107:2013-2021.
2. Fischer, K., P. Hoffmann, S. Voelkl, N. Meidenbauer, J. Ammer, M. Edinger, E. Gottfried, S. Schwarz, G. Rothe, S. Hoves, K. Renner, B. Timischl, A. Mackensen, L. Kunz-Schughart, R. Andreesen, S. W. Krause, M. Kreutz. 2007. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109:3812-3819.
3. Dietl, K., K. Renner, K. Dettmer, B. Timischl, K. Eberhart, C. Dorn, C. Hellerbrand, M. Kastenberger, L. A. Kunz-Schughart, P. J. Oefner, R. Andreesen, E. Gottfried, M. P. Kreutz. 2010. Lactic acid and acidification inhibit TNF secretion and glycolysis of human monocytes. J Immunol 184:1200-1209.
4. Mendler AN, Hu B, Prinz PU, Kreutz M (P1), Gottfried E, Noessner E .Tumor lactic acidosis suppresses CTL function by inhibition of p38 and JNK/c-Jun activation. Int J Cancer 2011, Sep 2. Int J Cancer. Aug 1;131(3):633-40. doi: 10.1002
5. Moser C, Lang SA (P6), Hackl C, Zhang H, Lundgren K, Hong V, McKenzie A, Weber B, Park JS, Schlitt HJ, Geissler EK, Jung YD, Stoeltzing O. Oncogenic MST1R Activity in Pancreatic and Gastric Cancer Represents a Valid Target of HSP90 Inhibitors. Anticancer Res. 2012 Feb;32(2):427-37.
6. Gottfried E (P1), Kreutz M (P1), Mackensen A (P3), Tumor metabolism as modulator of immune response and tumor progression. Seminars in Cancer Biology, 2012 Aug;22(4):335-41 (Review)
7. Moser C, Ruemmele P, Gehmert S, Schenk H, Kreutz M (P1), Mycielska ME, Hackl C, Kroemer A, Schnitzbauer AA, Stoeltzing O, Schlitt HJ, Geissler EK, Lang SA (2012). STAT5b as molecular target in pancreatic cancer–inhibition of tumor growth, angiogenesis, and metastases. Neoplasia. 2012 Oct;14(10):915-25
8. Kreutz M (P1), Karrer S, Hoffmann P, Gottfried E, Szeimies RM, Hahn J, Edinger M, Landthaler M, Andreesen R, Merad M, Holler E (2012). Whole-Body UVB Irradiation during Allogeneic Hematopoietic Cell Transplantation Is Safe and Decreases Acute Graft-versus-Host Disease. J. Invest. Dermatol. Jan;132(1):179-87. (IF 6.2)
9. Ullrich E, Bosch J, Aigner M, Voelkl S, Kroeger I, Hoffmann P, Kreutz M (P1), Dudziak D, Gerbitz A (2012). Advances in cellular therapy: 6th international symposium on the clinical use of cellular products, March 24 and 25, 2011, Erlangen, Germany. Cancer Immunol Immunother. Mar;61(3):433-43.
10. Chirasani SR, Leukel P, Gottfried E, Hochrein J, Stadler K, Neumann B, Oefner PJ (P7), Gronwald W (CP), Bogdahn U, Hau P, Kreutz M* (P1), Grauer OM* (2012). Diclofenac inhibits lactate formation and efficiently counteracts local immune suppression in a murine glioma model. Int J Cancer. 2013 Feb 15;132(4):843-53. *M.K. and O.M.G. contributed equally to this work
11. Gottfried E, Lang SA (P6), Bosserhoff AK (P2), Gronwald W (CP), …, Hau P, Dettmer K (CP), Oefner PJ (P7), Andreesen R, Kreutz M (P1). Diclofenac targets glycolysis via MYC and HIF regulation. PLOS ONE 2013 Jul 9;8(7).
12. Dettmer K, Vogl FC, Ritter AP, Zhu W, Nürnberger N, Kreutz M, Oefner PJ, Gronwald W, Gottfried E. Distinct metabolic differences between various human cancer and primary cells. Electrophoresis. 2013 Jul 16.
13. Seliger C, Leukel P, Moeckel S, Jachnik B, Lottaz C, Kreutz M, Brawanski A, Proescholdt M, Bogdahn U, Bosserhoff AK, Vollmann-Zwerenz A, Hau P (2013). Lactate-Modulated Induction of THBS-1 Activates Transforming Growth Factor (TGF)-beta2 and Migration of Glioma Cells In Vitro. PLOS One. Nov 1;8(11). (IF 3.5)
14. 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 M, Edinger M, Rehli M, for the FANTOM consortium. Transcription and enhancer profiling in human monocyte subsets. Blood 2014 24;123(17).
15. Krupar R, Robold K, Gaag D, Spanier G, Kreutz M, Renner K, Hellerbrand C, Hofstaedter F, Bosserhoff AK. Immunologic and metabolic characteristics of HPV-negative and HPV-positive head and neck squamous cell carcinomas are strikingly different. Virchows Arch. 2014 Sep;465(3):299-312.
16. Peter K, Rehli M, Singer K, Renner K, Kreutz M. Lactic acid delays the inflammatory response of human monocytes. BBRC 2015 in press
Dr. Katrin Singer
| Anna Höhn