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

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

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch
• Notes: Journal of experimental medicine. - 217, 8 (2020) , e20191920, ISSN: 1540-9538

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2020
• Creator: Manzo, Teresa ; Tucci, Sara ; Nezi, Luigi

Further information

• DOI: 10.1084/jem.20191920
• URN: urn:nbn:de:bsz:25-freidok-1697967
• Rights: Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 15.08.2025, 7:31 AM CEST