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Magdalena Huber: CD8⁺ T cell dysfunction mediated by ovarian carcinoma ascites: role of lipid metabolism

AIM: Altered lipid metabolism is among the most prominent metabolic alterations in cancer. We observed that heightened cholesterol levels in HGSC ascites contribute to the impaired CD8⁺ T cell activation, proliferation, and expression of the transcription factor Interferon Regulatory factor (IRF) 4. Here, we hypothesize that increased cholesterol amounts in HGSC ascites suppress cholesterol and fatty acid synthesis in CD8⁺ T cells in a negative feedback loop. To decipher the role of lipid metabolisms for T cell responses in the microenvironment we will comprehensively analyze ascites-mediated changes in the cellular and membrane lipid content, and TCR signaling. The cholesterol-mediated effects on CAR T-cell activation will be examined.

STATE of the ART: CD8⁺ Cytotoxic T Lymphocytes (CTLs), which produce IFN-γ, TNF, and cytotoxic molecules including perforin and granzymes display specific cytotoxicity and long-term memory against tumor cells, and therefore they are the most efficient effectors in the eradication and protection from relapse. However, tumors induce a dysfunctional state in CTLs termed exhaustion which is characterized by an impaired effector function, reduced survival, and increased expression of inhibitory receptors including checkpoint inhibitors: programmed cell death 1 (PD1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). However, immune checkpoint blockade (ICB) shows only limited response in OC patients indicating that additional mechanisms hamper the CTL response in HGSC.