Abstract 198: Selective targeting of endothelial mTORC1 reduces transendothelial fatty acid delivery to improve anti-tumor immunity and suppress metastatic outgrowth

Abstract Tumor metastasis requires sufficient nutrients to support outgrowth of disseminated tumor cells. Cancer cells utilize fatty acids as a key source of energy and biomass, but these nutrients impair the cytotoxic activities of T cells, serving to support metastatic progression. Blood is a rich source of fatty acids, but the vascular endothelium serves as a barrier to limit access to the surrounding tumor tissue. However, it is unclear how long-chain fatty acid delivery to early metastatic tumors is regulated. Here, we report that endothelial mTORC1 promotes transport of fatty acids into developing metastatic tumors, leading to reduced anti-tumor immune responses and improved outgrowth. Using a murine model of metastatic outgrowth in the lung, tumor burden was significantly reduced upon targeted deletion of Raptor, an essential component of the mTORC1 complex, in endothelial cells (RptorECKO). We employed a multifaceted approach using metabolomics, transcriptomics, and molecular assays to identify a Raptor/mTORC1-mediated mechanism of transendothelial fatty acid transport via RAB and CLSTN1 cargo trafficking. In vivo uptake of a fluorescent palmitic acid analog in tumor cells and T cells was reduced in RptorECKO lung metastatic tumors, which correlated with improved markers of cytotoxicity. Combination of low-dose RAD001/everolimus, which selectively inhibits mTORC1 in endothelial cells, with anti-PD1 reduces metastatic disease and impairs long-chain fatty acid uptake in T cells, corresponding to improved anti-tumor immunity. These findings describe a novel mechanism of transendothelial fatty acid transportation during metastatic outgrowth, supporting future development of therapeutic strategies to target endothelial mTORC1 activity. Citation Format: Deanna N. Edwards, Shan Wang, Wenqiang Song, Laura C. Kim, Yoonha Hwang, Jin Chen. Selective targeting of endothelial mTORC1 reduces transendothelial fatty acid delivery to improve anti-tumor immunity and suppress metastatic outgrowth abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 198.