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Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8+ T cells
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| Veröffentlicht in: | Journal of experimental medicine 217, 8 (2020), e20191920 |
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| Personen und Körperschaften: | , , |
| Titel: | Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8+ T cells/ Teresa Manzo, Sara Tucci, Luigi Nezi |
| Format: | E-Book Sonderdruck |
| Sprache: | Englisch |
| veröffentlicht: |
New York, NY
Rockefeller Univ. Press
2020
Freiburg Albert-Ludwigs-Universität Freiburg 2020 |
| Gesamtaufnahme: |
Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8+ T cells; 217, 8 (2020), e20191920
|
| Quelle: | Verbunddaten SWB Lizenzfreie Online-Ressourcen |
| Zusammenfassung: | 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 |
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| Umfang: | 1 Online-Ressource (28 Seiten); Illustrationen, Diagramme |
| ISSN: |
1540-9538
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| DOI: | 10.1084/jem.20191920 |