TY - JOUR
T1 - Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic cd8+ t cells
AU - Manzo, Teresa
AU - Prentice, Boone M.
AU - Anderson, Kristin G.
AU - Raman, Ayush
AU - Schalck, Aislyn
AU - Codreanu, Gabriela S.
AU - Nava Lauson, Carina B.
AU - Tiberti, Silvia
AU - Raimondi, Andrea
AU - Jones, Marissa A.
AU - Reyzer, Michelle
AU - Bates, Breanna M.
AU - Spraggins, Jeffrey M.
AU - Patterson, Nathan H.
AU - McLean, John A.
AU - Rai, Kunal
AU - Tacchetti, Carlo
AU - Tucci, Sara
AU - Wargo, Jennifer A.
AU - Rodighiero, Simona
AU - Clise-Dwyer, Karen
AU - Sherrod, Stacy D.
AU - Kim, Michael
AU - Navin, Nicholas E.
AU - Caprioli, Richard M.
AU - Greenberg, Philip D.
AU - Draetta, Giulio
AU - Nezi, Luigi
N1 - Funding Information:
This work was supported by the University of Texas MD Anderson Cancer Center Pancreatic Moon Shot to G. Draetta, Cancer Prevention and Research Institute of Texas grant RP160471 to G. Draetta, US Department of Defense grant W81XWH-11-1-0418 to G. Draetta, Associazione Italiana per la Ricerca sul Cancro StartUp grant to T. Manzo and core funding from IRCCS European Institute of Oncology to L. Nezi. IMS research was performed in the laboratory of R.M. Caprioli and supported in part by National Institutes of Health/National Institute of General Medical Sciences P41 GM103391-08 and National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases F32 FDK105841A (B.M. Prentic). Some of this research was performed at the MD Anderson Cancer Center Flow Cytometry and Cellular Imaging Facility, which is supported by National Cancer Institute grant P30CA016672. The work was also supported by National Cancer Institute grant CA33084 to P.D. Greenberg. This work was partially supported by the Ministero della Salute with Ricerca Corrente and 5x1000 funds.
Publisher Copyright:
© 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/).
PY - 2020/8/3
Y1 - 2020/8/3
N2 - 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.
AB - 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.
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U2 - 10.1084/jem.20191920
DO - 10.1084/jem.20191920
M3 - Article
C2 - 32491160
AN - SCOPUS:85085960472
SN - 0022-1007
VL - 217
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 8
M1 - e20191920
ER -