Einfluss von MTA auf die Differenzierung und Reifung humaner Monozyten zu dendritischen Zellen in vitro
By modulating their metabolism malignant cells often gain advantage compared to their surrounding tissue. Tumor cells for example show an altered polyamine synthesis: various tumors are deficient for the enzyme methylthioadenosin-phosphorylase which leads to an extracellular accumulation of 5'-deoxy-5'-methythioadenosin (MTA). Since MTA is known to be immunomodulatory, the impact of MTA on the maturation and function of human dendritic cells (DCs) was analyzed in this study. MTA inhibited the
... MTA inhibited the expression of important DC surface molecules. Besides this regulatory effect on the DC maturation the presence of 150 µM MTA also suppressed the IL-12 production of these cells. DCs pretreated with MTA showed an impaired ability to induce an allogeneic T-cell proliferation in a mixed lymphocyte reaction (MLR). The presence of MTA in the MLR lead to a reduced proliferation of T-cells. Furthermore, MTA suppressed the proliferation of T-cells after polyclonal stimulation which demonstrated an impact of MTA on both DCs and T-cells. Moreover, MTA induced a down-regulation of the mRNA expression of important components involved in antigen-processing like TAP1, TAP2 and LMP2 which in part could also be proved at the protein level. Altogether MTA suppressed the maturation of DC and impaired their function as antigen presenting cells. Due to these results the secretion of MTA represents an immune escape mechanism providing a survival advantage for tumor cells. Hence, further research on tumor metabolism and its influence on the human immune system will be necessary to create a successful anti-tumor therapy. Future experiments should include analyses concerning the mechanism underlying the effect of MTA on DCs and other immune cells.