Necrosis associated factors (S100A4 and uric acid) promote accumulation of MSCs which induce IL10+/IDO+ lymphocytes (TUM7P.949)

Abstract Necrosis with subsequent release of damage-associated molecular patterns (DAMPs) is a characteristic feature of advanced solid tumors. DAMPs impact the tumor-microenvironment stimulating tumor-associated cells like mesenchymal stromal cells (MSCs). Tumor-infiltrating-MSCs are associated with tumor progression and metastasis. Oxidized DAMPs lose their stimulatory capacity on MSCs. As a DAMP-member S100A4 is sensitive to oxidation while uric acid (UA) acts as an antioxidant. We tested these two DAMP-members separately and in combination for their biologic activity on MSCs. S100A4 and UA showed a dose-dependent chemotactic activity on MSCs with synergistic effects when both DAMPs were combined. Substituting for UA, alternative antioxidants (Vitamin-C, dithiothreitol, and acetylcystein) had also a comparable synergistic effect on the chemotactic activity of S100A4, emphasizing the reducing potential of UA being responsible for the observed synergy. Yet, S100A4 and UA inhibited MSC proliferation without impacting their viability. Nevertheless, in the presence of S100A4 or UA, MSCs gained immunosuppressive capacities by inducing IL-10 and indoleamine dioxygenase expressing lymphocytes. We characterized S100A4 and UA as necrosis-associated factors playing a crucial role within MSC biology and thus immunoregulation. Our results have implications for therapeutic approaches targeting the tumor microenvironment and addressing the immunosuppressive nature of necrotic tumor.