Lipids in ovarian cancer ascites impair T cell function by disrupting TCR dynamics 9157

Abstract Description T cell therapies show little success in treating ovarian cancer; therefore, it is crucial to understand the barriers they confront. Most late-stage patients form ascites, which act as a liquid tumor environment. Using patient acelluar ovarian cancer ascites fluid (aOCA) as an ex vivo model of ovarian cancer, we show that aOCA impair T cell activation at early TCR signaling events. Removing lipids from aOCA partially rescues this activation deficit. Informed by these data, we hypothesized that lipids in aOCA disrupt TCR dynamics by altering the overall lipid composition and membrane features. Using untargeted lipidomics, we determine that T cells activated in aOCA are enriched in phosphatidylcholine species. Imaging using the membrane dye C-Laurdan showed that T cell membrane order is increased in aOCA but not delipidated (DL) aOCA. High resolution imaging revealed that immune synapse formation is similar in aOCA and DL aOCA; however, TCR clusters are smaller and less frequent in aOCA. TCR clustering is impacted by internalization and recycling. Accordingly, we find that TCR internalization is intact, but recycling is impaired in aOCA. Together, our data demonstrate that lipids in aOCA reduce TCR recycling and cluster size at the immune synapse, resulting in severe activation defects. These data showcase a previously uninvestigated mechanism of T cell dysfunction in aOCA and suggest the use of pre-activated T cell therapies to improve therapeutic efficacy in ovarian cancer. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)