Uptake of long-chain fatty acids from the bone marrow suppresses CD8+ T-cell metabolism and function in multiple myeloma
Author
Gudgeon, NancyGiles, 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
Publication date
2023-10-24
Metadata
Show full item recordAbstract
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.Citation
Gudgeon N, Giles H, Bishop EL, Fulton-Ward T, Escribano-Gonzalez C, Munford H, James-Bott A, Foster K, Karim F, Jayawardana D, Mahmood A, Cribbs AP, Tennant DA, Basu S, Pratt G, Dimeloe S. Uptake of long-chain fatty acids from the bone marrow suppresses CD8+ T-cell metabolism and function in multiple myeloma. Blood Adv. 2023 Oct 24;7(20):6035-6047. doi: 10.1182/bloodadvances.2023009890. PMID: 37276076; PMCID: PMC10582277.Type
ArticleAdditional Links
https://ashpublications.org/bloodadvancesPMID
37276076Journal
Blood AdvancesPublisher
American Society of Hematologyae974a485f413a2113503eed53cd6c53
10.1182/bloodadvances.2023009890