Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic cd8+ t cells: Journal of Experimental Medicine

T. Manzo, B.M. Prentice, K.G. Anderson, A. Raman, A. Schalck, G.S. Codreanu, C.B. Nava Lauson, S. Tiberti, A. Raimondi, M.A. Jones, M. Reyzer, B.M. Bates, J.M. Spraggins, N.H. Patterson, J.A. McLean, K. Rai, C. Tacchetti, S. Tucci, J.A. Wargo, S. RodighieroK. Clise-Dwyer, S.D. Sherrod, M. Kim, N.E. Navin, R.M. Caprioli, P.D. Greenberg, G. Draetta, L. Nezi

Research output: Contribution to journalArticlepeer-review

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. © 2020 Manzo et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
Original languageEnglish
JournalJ. Exp. Med.
Volume217
Issue number8
DOIs
Publication statusPublished - 2020

Keywords

  • CD8 antigen
  • long chain acyl coenzyme A dehydrogenase
  • long chain fatty acid
  • very long chain fatty acid
  • animal experiment
  • animal model
  • animal tissue
  • Article
  • cancer immunotherapy
  • CD8+ T lymphocyte
  • cell death
  • cell function
  • cell reprogramming technique
  • cell survival
  • controlled study
  • down regulation
  • fatty acid metabolism
  • human
  • lipid level
  • lipid metabolism
  • lipid storage
  • lipotoxicity
  • mouse
  • nonhuman
  • pancreas adenocarcinoma
  • priority journal
  • tumor microenvironment

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