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

• Published in: The Journal of experimental medicine Vol. 217; no. 8
• Main Authors: Manzo, Teresa, Prentice, Boone M., Anderson, Kristin G., Raman, Ayush, Schalck, Aislyn, Codreanu, Gabriela S., Nava Lauson, Carina B., Tiberti, Silvia, Raimondi, Andrea, Jones, Marissa A., Reyzer, Michelle, Bates, Breanna M., Spraggins, Jeffrey M., Patterson, Nathan H., McLean, John A., Rai, Kunal, Tacchetti, Carlo, Tucci, Sara, Wargo, Jennifer A., Rodighiero, Simona, Clise-Dwyer, Karen, Sherrod, Stacy D., Kim, Michael, Navin, Nicholas E., Caprioli, Richard M., Greenberg, Philip D., Draetta, Giulio, Nezi, Luigi
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 03.08.2020
• Subjects: Acyl-CoA Dehydrogenase, Long-Chain - biosynthesis; Acyl-CoA Dehydrogenase, Long-Chain - genetics; Animals; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - pathology; Down-Regulation; Fatty Acids - genetics; Fatty Acids - metabolism; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Lymphocytes, Tumor-Infiltrating - metabolism; Lymphocytes, Tumor-Infiltrating - pathology; Metabolism; Mice; Mice, Mutant Strains; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Pancreas - metabolism; Pancreas - pathology; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Tumor Immunology; Tumor Microenvironment
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20191920

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