Modulation of T cell metabolism to restore immune cell effector functions against high-grade serous ovarian cancer

• Applicant: Dr. Janna Heide
• Subject Area: Gynaecology and Obstetrics
• Term: from 2021 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 459327389

Ovarian cancer is the second deadliest gynecological malignancy with an estimated 7000 new cases and about 5400 deaths each year in Germany. High-grade serous ovarian cancer (HGSOC) is the most common and deadliest subtype. Despite new therapeutic approaches, the overall survival of patients with HGSOC has only slightly improved in the last decades.High numbers of infiltrating T cells in HGSOC correlate with improved patient outcome. This indicates that T cells play pivotal roles in the clinical course of ovarian cancer. However, immune therapies, such as immune checkpoint inhibitors, only showed modest results in the treatment of HGSOC, despite subsequent T cell activation. Why these promising therapies have not been therapeutically successful, remains unclear. However, a variety of studies were able to demonstrate that metabolic influences of the tumor microenvironment (TME), such as deprivation of glucose, and discharge of metabolic byproducts, such as lactate, can inhibit T cell effector functions.Adipocytes were shown to play an essential role in tumor progression by providing tumor cells with energy and signaling lipids. A connection between the loss of T cell functions and adipocytes was demonstrated, which is presumably due to metabolic modulation. However, it is uncertain how adipocytes and HGSOC cells modulate T cell metabolism and how these altered metabolic pathways decrease anti-tumor immunity.The objectives of the proposed project are to characterize infiltrating T cells in the TME of HGSOC and to investigate influences between HGSOC cells and adipocytes on T cell metabolism and effector functions. In order to achieve these objectives, innovative methods such as mass cytometry by time-of-flight and metabolomics will be applied which allow a detailed characterization of immune cells and cell metabolism. Furthermore, an organotypic 3D culture will enable the study of reciprocal influences between tumor cells, adipocytes, and T cells to detect mechanisms that inhibit anti-tumor responses. The modulation of inhibitory metabolic mechanisms could restore the function of T cells and provide essential information for the development of innovative and efficacious therapeutic approaches to ovarian cancer.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Ernst Lengyel