Fatty acid metabolism of myeloid suppressor cells in tumor microenvironment as potential therapeutic target.

• Applicant: Dr. Rainer Glauben
• Subject Area: Gastroenterology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 445460773

The tumor microenvironment (TME) is characterized by a unique metabolic milieu. In our previous studies, we identified a modulating effect of oleic acid as unsaturated fatty acid on the functional polarization of myeloid cells into a monocytic MDSC- as well as a TAM-like phenotype. The development of this phenotype could be directly linked to the formation of lipid droplets inside these cells and an increased fatty acid oxidation compared to control groups. Since DGAT is a key enzyme for the formation of lipid droplets, we hypothesize that the phenotype of TAM and thus the tumor-escape from the immune system depends on the DGAT activity and consecutively the lipid metabolism of these tumor-infiltrating myeloid cells. This metabolic pathway can be targeted by specific chemical inhibitors.Define the effects of diglyceride acyltransferase inhibitors (iDGAT) on tumor growth and tumor infiltrating myeloid cells and T cells. Therefore, inoculation-, chemically induced, genetic as well as humanized murine cancer models will be applied and treated with cell-specific iDGAT (packed in a liposome carrier system). Tumor onset and growth will be determined and the myeloid as well as T cell compartment will be analyzed via mass cytometry (amongst others). Additionally, the effects of a combined approach of iDGAT and checkpoint inhibitors in murine tumor models, targeting myeloid suppression and T cell exhaustion simultaneously will be determined.Furthermore, we will decipher lipid droplet-related intracellular pathways and the associated metabolic machinery, which drive the regulatory phenotype of myeloid cells in the fatty acid-enriched tumor microenvironment. Therefore we will generate CRISPR/Cas9-based DGAT1 and DGAT2-KO-macrophages. These will be extensively analyzed using state-of-the-art approaches as lipidomics, proteomics as well as transcriptomics to determine the phenotype induced by the lipid droplet-dependent fatty acid metabolism.Finally, we will translate these results to the human situation and plan to define the exact phenotype of lipid droplet bearing TAM in human tumor samples and demonstrate the link between the cellular phenotype and the pathogenesis of cancer patients. Therefore, we will analyze colorectal cancer samples for the presence of lipid droplet bearing macrophages with regard to their phenotype based on extensive immunophenotyping via immunohistochemistry and imaging mass cytometry. Ultimately, deciphering the downstream effects of DGAT1 and 2 on a functional but also on a molecular level, will determine the impact of the identified mechanisms and hence reveal potential novel targets in tumor therapy.

• DFG Programme: Research Grants
• International Connection: China
• Cooperation Partner: Zhihai Qin, Ph.D.