Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8+ T cells
Open Access
- 3 June 2020
- journal article
- research article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 217 (8)
- https://doi.org/10.1084/jem.20191920
Abstract
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.Keywords
Funding Information
- University of Texas MD Anderson Cancer Center
- Cancer Prevention and Research Institute of Texas (RP160471)
- U.S. Department of Defense (W81XWH-11-1-0418)
- Associazione Italiana per la Ricerca sul Cancro
- National Institutes of Health
- National Institute of General Medical Sciences (P41 GM103391-08)
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (F32 FDK105841A)
- National Cancer Institute (P30CA016672)
- National Cancer Institute (CA33084)
- Ministero della Salute
- IRCCS European Institute of Oncology
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