Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8+ T cells
| Autor: | Gabriela S. Codreanu, Aislyn Schalck, Nathan Heath Patterson, John A. McLean, Breanna M. Bates, Michelle L. Reyzer, Luigi Nezi, Nicholas Navin, Giulio Draetta, Ayush T. Raman, Marissa A. Jones, Silvia Tiberti, Sara Tucci, Simona Rodighiero, Philip D. Greenberg, Karen Clise-Dwyer, Michael P. Kim, Teresa Manzo, Kunal Rai, Carlo Tacchetti, Richard M. Caprioli, Andrea Raimondi, Kristin G. Anderson, Stacy D. Sherrod, Boone M. Prentice, Jennifer A. Wargo, Carina B. Nava Lauson, Jeffrey M. Spraggins |
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| Přispěvatelé: | Manzo, T, Prentice, Bm, Anderson, Kg, Raman, A, Schalck, A, Codreanu, G, Nava Lauson, Cb, Tiberti, S, Raimondi, A, Jones, Ma, Reyzer, M, Bates, Bm, Spraggins, Jm, Patterson, Nh, Mclean, Ja, Rai, K, Tacchetti, C, Tucci, S, Wargo, Ja, Rodighiero, S, Clise-Dwyer, K, Sherrod, Sd, Kim, M, Navin, Ne, Caprioli, Rm, Greenberg, Pd, Draetta, G, Nezi, L |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Tumor Immunology T cell Immunology Down-Regulation CD8-Positive T-Lymphocytes Article Gene Expression Regulation Enzymologic 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Lymphocytes Tumor-Infiltrating medicine Tumor Microenvironment Immunology and Allergy Cytotoxic T cell Animals Pancreas Tumor microenvironment Fatty acid metabolism Acyl-CoA Dehydrogenase Long-Chain Fatty Acids Lipid metabolism Mice Mutant Strains Cell biology Neoplasm Proteins Gene Expression Regulation Neoplastic Pancreatic Neoplasms 030104 developmental biology medicine.anatomical_structure Metabolism Lipotoxicity chemistry Tumor progression 030220 oncology & carcinogenesis CD8 Carcinoma Pancreatic Ductal |
| Zdroj: | The Journal of Experimental Medicine |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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