Project Details
Projekt
Differentiation and activation of immune cells in the tumor microenvironment: role of tumor-derived lactate in immunomodulation in vitro and in vivo
Subject Area
Hematology, Oncology
Term
from 2011 to 2018
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 190230491
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 offtarget 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.
DFG Programme
Clinical Research Units
