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 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 03, 2020
- Source ID
- 10.1084/jem.20191920
Entities
People
- Aislyn Schalck
- Andrea Raimondi
- Ayush Raman
- Boone M Prentice
- Breanna M. Bates
- Carina B. Nava Lauson
- Carlo Tacchetti
- Gabriela S. Codreanu
- Giulio F Draetta
- Jeffrey M. Spraggins
- Jennifer Wargo
- John A. McLean
- Karen Clise-Dwyer
- Kristin G Anderson
- Kunal Rai
- Luigi Nezi
- Marissa A Jones
- Michael Kim
- Michelle Reyzer
- Nathan Heath Patterson
- Nicholas Navin
- Philip D. Greenberg
- Richard M. Caprioli
- Sara Tucci
- Silvia Tiberti
- Simona Rodighiero
- Stacy Sherrod
- Teresa Manzo
Organizations
- AIRC - The Italian Foundation for Cancer Research
- Cancer Prevention and Research Institute of Texas
- European Institute of Oncology
- Fred Hutchinson Cancer Center
- Ministry of Health of Italy
- National Cancer Institute
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute of General Medical Sciences
- National Institutes of Health
- The University of Texas MD Anderson Cancer Center
- United States Department of Defense
- University of Freiburg
- University of Texas at Austin
- University of Washington
- Vanderbilt University