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Uptake of long-chain fatty acids from the bone marrow suppresses CD8(+) T-cell metabolism and function in multiple myeloma
T cells demonstrate impaired function in multiple myeloma (MM) but suppressive mechanisms in the bone marrow microenvironment remain poorly defined. We observe that bone marrow CD8(+) T-cell function is decreased in MM compared with controls, and is also consistently lower within bone marrow samples...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society of Hematology
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10582277/ https://www.ncbi.nlm.nih.gov/pubmed/37276076 http://dx.doi.org/10.1182/bloodadvances.2023009890 |
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author | Gudgeon, Nancy Giles, Hannah Bishop, Emma L. Fulton-Ward, Taylor Escribano-Gonzalez, Cristina Munford, Haydn James-Bott, Anna Foster, Kane Karim, Farheen Jayawardana, Dedunu Mahmood, Ansar Cribbs, Adam P. Tennant, Daniel A. Basu, Supratik Pratt, Guy Dimeloe, Sarah |
author_facet | Gudgeon, Nancy Giles, Hannah Bishop, Emma L. Fulton-Ward, Taylor Escribano-Gonzalez, Cristina Munford, Haydn James-Bott, Anna Foster, Kane Karim, Farheen Jayawardana, Dedunu Mahmood, Ansar Cribbs, Adam P. Tennant, Daniel A. Basu, Supratik Pratt, Guy Dimeloe, Sarah |
author_sort | Gudgeon, Nancy |
collection | PubMed |
description | T cells demonstrate impaired function in multiple myeloma (MM) but suppressive mechanisms in the bone marrow microenvironment remain poorly defined. We observe that bone marrow CD8(+) T-cell function is decreased in MM compared with controls, and is also consistently lower within bone marrow samples than in matched peripheral blood samples. These changes are accompanied by decreased mitochondrial mass and markedly elevated long-chain fatty acid uptake. In vitro modeling confirmed that uptake of bone marrow lipids suppresses CD8(+) T function, which is impaired in autologous bone marrow plasma but rescued by lipid removal. Analysis of single-cell RNA-sequencing data identified expression of fatty acid transport protein 1 (FATP1) in bone marrow CD8(+) T cells in MM, and FATP1 blockade also rescued CD8(+) T-cell function, thereby identifying this as a novel target to augment T-cell activity in MM. Finally, analysis of samples from cohorts of patients who had received treatment identified that CD8(+) T-cell metabolic dysfunction resolves in patients with MM who are responsive to treatment but not in patients with relapsed MM, and is associated with substantial T-cell functional restoration. |
format | Online Article Text |
id | pubmed-10582277 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | The American Society of Hematology |
record_format | MEDLINE/PubMed |
spelling | pubmed-105822772023-10-19 Uptake of long-chain fatty acids from the bone marrow suppresses CD8(+) T-cell metabolism and function in multiple myeloma Gudgeon, Nancy Giles, Hannah Bishop, Emma L. Fulton-Ward, Taylor Escribano-Gonzalez, Cristina Munford, Haydn James-Bott, Anna Foster, Kane Karim, Farheen Jayawardana, Dedunu Mahmood, Ansar Cribbs, Adam P. Tennant, Daniel A. Basu, Supratik Pratt, Guy Dimeloe, Sarah Blood Adv Lymphoid Neoplasia T cells demonstrate impaired function in multiple myeloma (MM) but suppressive mechanisms in the bone marrow microenvironment remain poorly defined. We observe that bone marrow CD8(+) T-cell function is decreased in MM compared with controls, and is also consistently lower within bone marrow samples than in matched peripheral blood samples. These changes are accompanied by decreased mitochondrial mass and markedly elevated long-chain fatty acid uptake. In vitro modeling confirmed that uptake of bone marrow lipids suppresses CD8(+) T function, which is impaired in autologous bone marrow plasma but rescued by lipid removal. Analysis of single-cell RNA-sequencing data identified expression of fatty acid transport protein 1 (FATP1) in bone marrow CD8(+) T cells in MM, and FATP1 blockade also rescued CD8(+) T-cell function, thereby identifying this as a novel target to augment T-cell activity in MM. Finally, analysis of samples from cohorts of patients who had received treatment identified that CD8(+) T-cell metabolic dysfunction resolves in patients with MM who are responsive to treatment but not in patients with relapsed MM, and is associated with substantial T-cell functional restoration. The American Society of Hematology 2023-06-07 /pmc/articles/PMC10582277/ /pubmed/37276076 http://dx.doi.org/10.1182/bloodadvances.2023009890 Text en © 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Lymphoid Neoplasia Gudgeon, Nancy Giles, Hannah Bishop, Emma L. Fulton-Ward, Taylor Escribano-Gonzalez, Cristina Munford, Haydn James-Bott, Anna Foster, Kane Karim, Farheen Jayawardana, Dedunu Mahmood, Ansar Cribbs, Adam P. Tennant, Daniel A. Basu, Supratik Pratt, Guy Dimeloe, Sarah Uptake of long-chain fatty acids from the bone marrow suppresses CD8(+) T-cell metabolism and function in multiple myeloma |
title | Uptake of long-chain fatty acids from the bone marrow suppresses CD8(+) T-cell metabolism and function in multiple myeloma |
title_full | Uptake of long-chain fatty acids from the bone marrow suppresses CD8(+) T-cell metabolism and function in multiple myeloma |
title_fullStr | Uptake of long-chain fatty acids from the bone marrow suppresses CD8(+) T-cell metabolism and function in multiple myeloma |
title_full_unstemmed | Uptake of long-chain fatty acids from the bone marrow suppresses CD8(+) T-cell metabolism and function in multiple myeloma |
title_short | Uptake of long-chain fatty acids from the bone marrow suppresses CD8(+) T-cell metabolism and function in multiple myeloma |
title_sort | uptake of long-chain fatty acids from the bone marrow suppresses cd8(+) t-cell metabolism and function in multiple myeloma |
topic | Lymphoid Neoplasia |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10582277/ https://www.ncbi.nlm.nih.gov/pubmed/37276076 http://dx.doi.org/10.1182/bloodadvances.2023009890 |
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