Oxidation-specific epitopes as regulators of MDSC in cancer

The interaction of a tumor with the patients immune system is a complex process that involves cellular communication of cancer cells with cells of the innate and adaptive immune system. Dependent on the type of tumor, its immunogenicity, its vascularization state and the tumors ability to interact with the hematopoietic system, different immune cells home into the tumor microenvironment (TME). The specific composition of the tumor immune microenvironment determines the efficacy of the anti- tumor immune reaction and is an important indicator for the response of patients towards tumor immunotherapies. Certain tumors recruit high amounts of certain innate immune cells, so called myeloid-derived suppressor cells (MDSC) into the TME, which protect cancer cells from effective anti-tumor immune defense by blocking the tumor cell-killing activity of cytotoxic T cells. To do so, MDSC are activated in the TME, thereby acquiring a diverse set of immunosuppressive properties that interfere with T cell functionality. In this research project, the primary goal is the identification of distinct lipid species that mediate the activation process of MDSC in the TME. In first experiments, we found that certain oxidation-modified lipids accumulate in tumor-bearing mice and that MDSC in the TME produce high amounts of cell surface receptors that are known to bind this class of lipids. Furthermore, we found that when exposing MDSC to those lipids in vitro, they acquire potent T cell suppressive activities. To understand this lipid- mediated activation process of MDSC in more detail, we propose to i) identify oxidation-modified lipid species that accumulate in the TME of certain tumor models by unbiased approaches; ii) test the interaction of those lipid species with MDSC on a functional level and iii) analyze the role of oxidation- modified lipids regarding MDSC-mediated in vivo tumor progression and resistance mechanisms towards immunotherapeutic approaches. In summary, this research proposal is dedicated to unravel the mechanisms that underly the activation and acquisition of immunosuppression properties of MDSC by lipid oxidation products in the TME. Moreover, this study aims to clarify whether blocking the activation of MDSC by a reduction or neutralization of certain oxidized lipid species holds potential to increase the efficacy of immunotherapeutic approaches.