Abstract 1021: A novel interaction between hydrogen peroxide metabolism and LDL-uptake controls immunergulatory properties in human dendritic cells - Potential implications for tumor immune escape

Abstract

Abstract Introduction: Recent studies indicate that depletion of reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) may actually allow tumors to evade immunological rejection prompting us to analyze the impact of H2O2-depletion on dendritic cells (DCs) as they play a pivotal role in tumor immunology. Methods: Primary human monocytes from healthy donors were differentiated/maturated to DCs w/o concomitant enzymatic H2O2-depletion (i.e. purified catalase). DCs were then analyzed for the expression of typical maturation-markers (i.e. CD80/86) and their functionality (i.e. induction/suppression of T-cell proliferation, secretion of distinct cytokines). To identify the underlying mechanisms for the differences observed we analyzed the role of H2O2- and cholesterol-metabolism as they are interconnected in monocyte-driven phagocytosis. Results: Depletion of H2O2 not only impaired DC-maturation (i.e. impaired upregulation of CD80/86), but additionally induced immunosuppressive properties such as suppression of T-cell proliferation via IDO, both typical features of so called regulatory DCs found in the tumor-microenvironment. However, the impact of H2O2-depletion throughout DC differentiation/maturation appears to be rather complex: Thus differentiated/matured DCs did not only feature properties of pro-tumorigenic macrophages (i.e. CD163- and PAI-1-expression) but also were capable of inducing IL10/IL17 double-expressing T-cells which have been reported to contribute to tumor-immune-escape in AML. Paradoxically, extracellular H2O2-depletion resulted in increased intracellular H2O2-levels, and increased LDL uptake, which has been reported to potentially affect immunological tumor rejection. Finally, we were able to establish a direct link between H2O2-production, LDL uptake, and induction of immunosuppressive DCs as both, inhibition of LDL uptake and depletion of intracellular H2O2, restored maturation and abrogated immunosuppressive properties. Conclusion: Alongside with earlier findings such as the ability of hepatic stromal cells to induce myeloid-derived suppressor cells via contact-dependent H2O2-depletion, the here presented study sheds new light on the role of H2O2 in tumor-immunology. Importantly, our findings unravel a so far unrecognized interaction between H2O2- and LDL-metabolism controlling distinct properties in DCs, which might in return explain the association between lipid metabolism and impaired immunity in some tumors. Bearing in mind that tumors employ several mechanisms to deplete ROS incl. H2O2 we believe that these findings may contribute to the development of novel (immune-) therapeutic approaches for cancer patients. Citation Format: Ann-Katrin Menzner, Tanja Rottmar, Simon Voelkl, Jacobus J. Bosch, Dimitrios Mougiakakos, Andreas Mackensen, Yazid J. Resheq. A novel interaction between hydrogen peroxide metabolism and LDL-uptake controls immunergulatory properties in human dendritic cells - Potential implications for tumor immune escape [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1021.