Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8+ T cells

• DOI: 10.1084/jem.20191920
• Publication Date: 2020-06-03T13:32:48Z
• Authors: Teresa Manzo; Boone M. Prentice; Kristin G. Anderson; Ayush Raman; Aislyn Schalck; Gabriela S. Codreanu; Carina B. Nava La...; Silvia Tiberti; Andrea Raimondi; Marissa A. Jones; Michelle Reyzer; Breanna M. Bates; Jeffrey M. Spraggins; Nathan H. Patterson; John A. McLean; Kunal Rai; Carlo Tacchetti; Sara Tucci; Jennifer A. Wargo; Simona Rodighiero; Karen Clise-Dwyer; Stacy D. Sherrod; Michael Kim; Nicholas E. Navin; Richard M. Caprioli; Philip D. Greenberg; Giulio Draetta; Luigi Nezi
• Keywords: Lipotoxicity; Reprogramming

CD8+ T cells are master effectors of antitumor immunity, and their presence at tumor sites correlates with favorable outcomes. However, metabolic constraints imposed by the microenvironment (TME) can dampen ability to control progression. We describe lipid accumulation in TME areas pancreatic ductal adenocarcinoma (PDA) populated infiltrating both murine human tumors. In this lipid-rich but otherwise nutrient-poor TME, access using metabolism becomes particularly valuable for sustaining cell functions. Here, we found that intrapancreatic progressively accumulate specific long-chain fatty acids (LCFAs), which, rather than provide a fuel source, impair mitochondrial function trigger major transcriptional reprogramming pathways involved metabolism, subsequent reduction acid catabolism. particular, specifically exhibit down-regulation very-long-chain acyl-CoA dehydrogenase (VLCAD) enzyme, which exacerbates LCFAs (VLCFAs) mediate lipotoxicity. Metabolic tumor-specific through enforced expression ACADVL enabled enhanced intratumoral survival persistence an engineered mouse model PDA, overcoming one hurdles immunotherapy PDA.