Burn Baby Burn: Leveraging Fatty Acid Oxidation to Improve CD8+ T cell Efficacy Against Ovarian Cancer 2250461

Abstract

Abstract Introduction CD8+ T cell differentiation upon activation is heavily influenced by type and availability of local nutrients. However, when nutrients are limited such as in a tumor microenvironment (TME), it has a strong negative impact on cytotoxic T cell survival and differentiation. In the metabolically hostile TME, quick progression of CD8+ T cell exhaustion paired with the immune evasion mechanisms of cancer cells results in a subdued immune response and poor prognosis. This is particularly problematic in ovarian cancer, a prominent and highly fatal gynecologic malignancy characterized by tumor development within fat deposits such as the omentum. We hypothesize that using PPARα agonist Fenofibrate (FF) can increase T cell usage of local fats to drive them towards a memory phenotype, promoting survival in the TME and enhance antitumor properties. As memory T cell populations can persist for longer durations, selecting for this phenotype may generate better CD8+ T cell function and tumor control. This project characterizes how augmentation of fat burning metabolism can increase the potential of CD8+ T cells as a therapy protecting against ovarian cancer. Methods CD8+ T Cells were treated with FF to transcriptionally enhance metabolic machinery required to support increased fatty acid oxidation (FAO). Impact on T cell metabolism and cytotoxic capacity under in vitro conditions mimicking the TME were evaluated by flow cytometry and Seahorse Mitostress Test. T cell survival, function and protection were tested in vivo, and T cells were isolated and analyzed ex vivo via flow cytometry. Results T cells treated with FF show enhanced memory phenotype and fat uptake, reduced terminal exhaustion, and higher spare respiratory capacity compared to untreated controls in vitro. Ongoing studies are investigating the presence of these trends in vivo. Conclusion Our data suggests Fenofibrate may enhance success of adoptive cell transfer therapy by improving the survival and function of CD8+ T cells in the ovarian TME. Funding Source NIH (NIAID) RO1 grant: CA257954 Dartmouth TQCR Training Grant: T32CA260626 BioMT Core Facilities: NIH NIGMS grant P20-GM113132. The Norris Cotton Cancer Center Grant: 5P30CA023108. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)