Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8+ T cells
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 a...
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| Veröffentlicht in: | The Journal of experimental medicine Jg. 217; H. 8 |
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| Format: | Journal Article |
| Sprache: | Englisch |
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03.08.2020
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| ISSN: | 1540-9538, 1540-9538 |
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| 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. |
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| AbstractList | 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. 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.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. |
| Author | Bates, Breanna M Raimondi, Andrea Caprioli, Richard M Tucci, Sara Raman, Ayush Kim, Michael Patterson, Nathan H Jones, Marissa A McLean, John A Tacchetti, Carlo Sherrod, Stacy D Clise-Dwyer, Karen Tiberti, Silvia Schalck, Aislyn Wargo, Jennifer A Anderson, Kristin G Codreanu, Gabriela S Manzo, Teresa Rai, Kunal Navin, Nicholas E Nava Lauson, Carina B Greenberg, Philip D Reyzer, Michelle Rodighiero, Simona Prentice, Boone M Nezi, Luigi Draetta, Giulio Spraggins, Jeffrey M |
| Author_xml | – sequence: 1 givenname: Teresa surname: Manzo fullname: Manzo, Teresa organization: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX – sequence: 2 givenname: Boone M surname: Prentice fullname: Prentice, Boone M organization: Department of Biochemistry, Mass Spectrometry Research Center, Department of Chemistry, Department of Pharmacology and Medicine, Vanderbilt University, Nashville, TN – sequence: 3 givenname: Kristin G surname: Anderson fullname: Anderson, Kristin G organization: Departments of Medicine/Oncology and Immunology, University of Washington School of Medicine, Seattle, WA – sequence: 4 givenname: Ayush surname: Raman fullname: Raman, Ayush organization: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX – sequence: 5 givenname: Aislyn surname: Schalck fullname: Schalck, Aislyn organization: Department of Genetics and Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX – sequence: 6 givenname: Gabriela S surname: Codreanu fullname: Codreanu, Gabriela S organization: Center for Innovative Technology, Vanderbilt University, Nashville, TN – sequence: 7 givenname: Carina B surname: Nava Lauson fullname: Nava Lauson, Carina B organization: Department of Experimental Oncology, IRCCS European Institute of Oncology, Milano, Italy – sequence: 8 givenname: Silvia surname: Tiberti fullname: Tiberti, Silvia organization: Department of Experimental Oncology, IRCCS European Institute of Oncology, Milano, Italy – sequence: 9 givenname: Andrea surname: Raimondi fullname: Raimondi, Andrea organization: Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, San Raffaele Vita-Salute University, Milano, Italy – sequence: 10 givenname: Marissa A surname: Jones fullname: Jones, Marissa A organization: Department of Biochemistry, Mass Spectrometry Research Center, Department of Chemistry, Department of Pharmacology and Medicine, Vanderbilt University, Nashville, TN – sequence: 11 givenname: Michelle surname: Reyzer fullname: Reyzer, Michelle organization: Department of Biochemistry, Mass Spectrometry Research Center, Department of Chemistry, Department of Pharmacology and Medicine, Vanderbilt University, Nashville, TN – sequence: 12 givenname: Breanna M surname: Bates fullname: Bates, Breanna M organization: Departments of Medicine/Oncology and Immunology, University of Washington School of Medicine, Seattle, WA – sequence: 13 givenname: Jeffrey M surname: Spraggins fullname: Spraggins, Jeffrey M organization: Department of Biochemistry, Mass Spectrometry Research Center, Department of Chemistry, Department of Pharmacology and Medicine, Vanderbilt University, Nashville, TN – sequence: 14 givenname: Nathan H surname: Patterson fullname: Patterson, Nathan H organization: Department of Biochemistry, Mass Spectrometry Research Center, Department of Chemistry, Department of Pharmacology and Medicine, Vanderbilt University, Nashville, TN – sequence: 15 givenname: John A surname: McLean fullname: McLean, John A organization: Center for Innovative Technology, Vanderbilt University, Nashville, TN – sequence: 16 givenname: Kunal surname: Rai fullname: Rai, Kunal organization: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX – sequence: 17 givenname: Carlo surname: Tacchetti fullname: Tacchetti, Carlo organization: Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, San Raffaele Vita-Salute University, Milano, Italy – sequence: 18 givenname: Sara surname: Tucci fullname: Tucci, Sara organization: Laboratory of Clinical Biochemistry and Metabolism Center for Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany – sequence: 19 givenname: Jennifer A surname: Wargo fullname: Wargo, Jennifer A organization: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX – sequence: 20 givenname: Simona surname: Rodighiero fullname: Rodighiero, Simona organization: Department of Experimental Oncology, IRCCS European Institute of Oncology, Milano, Italy – sequence: 21 givenname: Karen surname: Clise-Dwyer fullname: Clise-Dwyer, Karen organization: Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX – sequence: 22 givenname: Stacy D surname: Sherrod fullname: Sherrod, Stacy D organization: Center for Innovative Technology, Vanderbilt University, Nashville, TN – sequence: 23 givenname: Michael surname: Kim fullname: Kim, Michael organization: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX – sequence: 24 givenname: Nicholas E surname: Navin fullname: Navin, Nicholas E organization: Department of Genetics and Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX – sequence: 25 givenname: Richard M surname: Caprioli fullname: Caprioli, Richard M organization: Department of Biochemistry, Mass Spectrometry Research Center, Department of Chemistry, Department of Pharmacology and Medicine, Vanderbilt University, Nashville, TN – sequence: 26 givenname: Philip D surname: Greenberg fullname: Greenberg, Philip D organization: Departments of Medicine/Oncology and Immunology, University of Washington School of Medicine, Seattle, WA – sequence: 27 givenname: Giulio surname: Draetta fullname: Draetta, Giulio organization: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX – sequence: 28 givenname: Luigi surname: Nezi fullname: Nezi, Luigi organization: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/32491160$$D View this record in MEDLINE/PubMed |
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| PublicationDate | 2020-08-03 |
| PublicationDateYYYYMMDD | 2020-08-03 |
| PublicationDate_xml | – month: 08 year: 2020 text: 2020-08-03 day: 03 |
| PublicationDecade | 2020 |
| PublicationPlace | United States |
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| PublicationTitle | The Journal of experimental medicine |
| PublicationTitleAlternate | J Exp Med |
| PublicationYear | 2020 |
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| Snippet | CD8+ T cells are master effectors of antitumor immunity, and their presence at tumor sites correlates with favorable outcomes. However, metabolic constraints... |
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| SubjectTerms | Acyl-CoA Dehydrogenase, Long-Chain - biosynthesis Acyl-CoA Dehydrogenase, Long-Chain - genetics Animals Carcinoma, Pancreatic Ductal - genetics Carcinoma, Pancreatic Ductal - metabolism Carcinoma, Pancreatic Ductal - pathology CD8-Positive T-Lymphocytes - metabolism CD8-Positive T-Lymphocytes - pathology Down-Regulation Fatty Acids - genetics Fatty Acids - metabolism Gene Expression Regulation, Enzymologic Gene Expression Regulation, Neoplastic Lymphocytes, Tumor-Infiltrating - metabolism Lymphocytes, Tumor-Infiltrating - pathology Mice Mice, Mutant Strains Neoplasm Proteins - biosynthesis Neoplasm Proteins - genetics Pancreas - metabolism Pancreas - pathology Pancreatic Neoplasms - genetics Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - pathology Tumor Microenvironment |
| Title | Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8+ T cells |
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