Reducing agents such as ascorbic acid or N-acetylcysteine support the chemotactic and proliferation-inducing effect of S100A4 on mesenchymal stromal cells (P2165)

Abstract

Chronic inflammatory response is found in most advanced solid tumors with subsequent necrosis associated with release of various damage-associated molecular patterns (DAMPs) including S100A4. Mesenchymal stromal cells (MSCs) seem to interfere with the anti-tumor-immune response resulting in a poor prognosis for cancer patients, given the immunosuppressive capacity of these cells. In previous experiments we already showed that S100A4 induces MSC proliferation with an optimum at 100ng/ml. We now tested higher S100A4 concentrations and observed a bimodal effect with a second optimum achieved when using more than 2000ng S100A4/ml. Furthermore, stimulation of MSCs with graded concentrations of S100A4 inhibited dose-dependently the proliferation of lymphocytes. Based on our previous observations that S100A4 activity is enhanced in the presence of uric acid, we now tested further reducing agents like ascorbic acid, dithiothreitole, and N-acetylcysteine and could demonstrate increased chemotactic activity of S100A4 on MSCs when mentioned antioxidants were present, while they had minimal - if any - effect by themselves. Considering that MSCs respond to necrosis-associated factors, we conclude that creating an oxidative environment could be one possible strategy to inactivate not only S100A4 but also further oxidation-sensitive DAMPs like HMGB1, which contribute to the immunosuppressive nature of tumor microenvironment.