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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| Published in | The Journal of experimental medicine Vol. 217; no. 8 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Rockefeller University Press
03.08.2020
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0022-1007 1540-9538 1540-9538 |
| DOI | 10.1084/jem.20191920 |
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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. Metabolic constrains induce transcriptional deregulation of CD8 + T cells in pancreatic tumor microenvironment, driving progressive dysfunction. Here, metabolic reprogramming through enforced very-long-chain acyl-CoA dehydrogenase expression enhances intratumor T cells survival and persistence, overcoming a major hurdle 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 | Nava Lauson, Carina B. Raimondi, Andrea Tucci, Sara Raman, Ayush Codreanu, Gabriela S. Prentice, Boone M. Kim, Michael Wargo, Jennifer A. Jones, Marissa A. Anderson, Kristin G. Greenberg, Philip D. Bates, Breanna M. Tacchetti, Carlo Clise-Dwyer, Karen Navin, Nicholas E. Tiberti, Silvia Schalck, Aislyn Patterson, Nathan H. McLean, John A. Caprioli, Richard M. Manzo, Teresa Rai, Kunal Reyzer, Michelle Rodighiero, Simona Spraggins, Jeffrey M. Nezi, Luigi Sherrod, Stacy D. Draetta, Giulio |
| AuthorAffiliation | 5 Departments of Medicine/Oncology and Immunology, University of Washington School of Medicine, Seattle, WA 11 Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 10 Laboratory of Clinical Biochemistry and Metabolism Center for Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany 2 Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 4 Clinical Research Division and Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA 8 Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, San Raffaele Vita-Salute University, Milano, Italy 6 Department of Genetics and Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 7 Center for Innovative Technology, Vanderbilt University, Nashville, TN 9 Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX 1 De |
| AuthorAffiliation_xml | – name: 2 Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX – name: 6 Department of Genetics and Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX – name: 5 Departments of Medicine/Oncology and Immunology, University of Washington School of Medicine, Seattle, WA – name: 3 Department of Biochemistry, Mass Spectrometry Research Center, Department of Chemistry, Department of Pharmacology and Medicine, Vanderbilt University, Nashville, TN – name: 4 Clinical Research Division and Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA – name: 7 Center for Innovative Technology, Vanderbilt University, Nashville, TN – name: 1 Department of Experimental Oncology, IRCCS European Institute of Oncology, Milano, Italy – name: 11 Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX – name: 10 Laboratory of Clinical Biochemistry and Metabolism Center for Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany – name: 8 Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, San Raffaele Vita-Salute University, Milano, Italy – name: 9 Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/32491160$$D View this record in MEDLINE/PubMed |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 A. Raman’s present address is Broad Institute of MIT and Harvard, Cambridge, MA. B.M. Prentice’s present address is Department of Chemistry, University of Florida, Gainesville, FL. Disclosures: Dr. Manzo, Dr. Anderson, Dr. Bates, Dr. Greenberg, and Dr. Nezi reported a patent to US Application No. 62/756,467 pending. Dr. McLean reported a patent to US application pending. Our laboratory is a Waters Center of Innovation (Waters Corporation) and an Agilent Thought Leader laboratory. These relationships did not influence the research described in the present manuscript. Dr. Wargo reported "other" from Genentech, GlaxoSmithKline, BMS, Merck, Illumina, and personal fees from AstraZeneca outside the submitted work; in addition, Dr. Wargo had a patent to PCT/US17/53.717 issued, "MD Anderson." Dr. Greenberg reported grants from Juno Therapeutics and personal fees from Juno Therapeutics during the conduct of the study; personal fees from Rapt Therapeutics, Elpiscience, Celsius, and Nextech outside the submitted work; and had a patent to Juno Therapeutics licensed. Dr. Draetta reported personal fees from Biovelocita, Nurix, Blueprint Medicines, Frontier Medicines, Orionis Biosciences, Tessa Therapeutics, Helsinn, Forma Therapeutics, Symphogen, Alligator, Taiho Pharmaceutical Co., and FIRC Institute of Molecular Oncology outside the submitted work. No other disclosures were reported. |
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Chem doi: 10.1021/ac800617s |
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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... Metabolic constrains induce transcriptional deregulation of CD8 + T cells in pancreatic tumor microenvironment, driving progressive dysfunction. Here,... |
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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 Metabolism Mice Mice, Mutant Strains Neoplasm Proteins - biosynthesis Neoplasm Proteins - genetics Pancreas - metabolism Pancreas - pathology Pancreatic Neoplasms - genetics Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - pathology Tumor Immunology Tumor Microenvironment |
| Title | Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8+ T cells |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/32491160 https://www.proquest.com/docview/2409191937 https://pubmed.ncbi.nlm.nih.gov/PMC7398173 |
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