Uptake of long-chain fatty acids from the bone marrow suppresses CD8+ T-cell metabolism and function in multiple myeloma

Nancy Gudgeon; Hannah Giles; Emma L Bishop; Taylor Fulton-Ward; Cristina Escribano-Gonzalez; Haydn Munford; Anna James-Bott; Kane Foster; Farheen Karim; Dedunu Jayawardana; Ansar Mahmood; Adam P Cribbs; Daniel A Tennant; Supratik Basu; Guy Pratt; Sarah Dimeloe

doi:10.1182/bloodadvances.2023009890

Uptake of long-chain fatty acids from the bone marrow suppresses CD8⁺ T-cell metabolism and function in multiple myeloma

Nancy Gudgeon, Hannah Giles, Emma L Bishop, Taylor Fulton-Ward, Cristina Escribano-Gonzalez, Haydn Munford, Anna James-Bott, Kane Foster, Farheen Karim, Dedunu Jayawardana, Ansar Mahmood, Adam P Cribbs, Daniel A Tennant, Supratik Basu, Guy Pratt, Sarah Dimeloe^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

23 Downloads (Pure)

Abstract

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.

Original language	English
Pages (from-to)	6035-6047
Number of pages	13
Journal	Blood Advances
Volume	7
Issue number	20
Early online date	5 Jun 2023
DOIs	https://doi.org/10.1182/bloodadvances.2023009890
Publication status	Published - 24 Oct 2023

Bibliographical note

Acknowledgments:
The authors gratefully acknowledge the contribution to this study made by the University of Birmingham’s Human Biomaterials Resource Centre, which was set up through the Birmingham Science City, Experimental Medicine Network of Excellence Project. This work was funded by Leukaemia UK John Goldman Fellowship and Blood Cancer UK Project grant 21007 (S.D.), which also supported N.G. and H.M. T.F.-W. was supported by a Cancer Research UK PhD Studentship. C.E.-G. and D.A.T. are supported by Cancer Research UK Programme grant C42109/A24757. H.G. is supported by a British Society of Haematology Early-Stage Research grant. A.P.C. is a recipient of a Medical Research Council Career Development Fellowship (MR/V010182/1).

Copyright:
© 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.

Access to Document

10.1182/bloodadvances.2023009890Licence: Creative Commons: Attribution-NonCommercial-NoDerivs (CC BY-NC-ND)

GudgeonN2023UptakeFinal published version, 1.26 MBLicence: Creative Commons: Attribution-NonCommercial-NoDerivs (CC BY-NC-ND)

Cite this

Gudgeon, N., Giles, H., Bishop, E. L., Fulton-Ward, T., Escribano-Gonzalez, C., Munford, H., James-Bott, A., Foster, K., Karim, F., Jayawardana, D., Mahmood, A., Cribbs, A. P., Tennant, D. A., Basu, S., Pratt, G., & Dimeloe, S. (2023). Uptake of long-chain fatty acids from the bone marrow suppresses CD8⁺ T-cell metabolism and function in multiple myeloma. Blood Advances, 7(20), 6035-6047. https://doi.org/10.1182/bloodadvances.2023009890

@article{7570e5f5eccc442f840107b3c47a3fe2,

title = "Uptake of long-chain fatty acids from the bone marrow suppresses CD8+ T-cell metabolism and function in multiple myeloma",

abstract = "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.",

author = "Nancy Gudgeon and Hannah Giles and Bishop, {Emma L} and Taylor Fulton-Ward and Cristina Escribano-Gonzalez and Haydn Munford and Anna James-Bott and Kane Foster and Farheen Karim and Dedunu Jayawardana and Ansar Mahmood and Cribbs, {Adam P} and Tennant, {Daniel A} and Supratik Basu and Guy Pratt and Sarah Dimeloe",

note = "Acknowledgments: The authors gratefully acknowledge the contribution to this study made by the University of Birmingham{\textquoteright}s Human Biomaterials Resource Centre, which was set up through the Birmingham Science City, Experimental Medicine Network of Excellence Project. This work was funded by Leukaemia UK John Goldman Fellowship and Blood Cancer UK Project grant 21007 (S.D.), which also supported N.G. and H.M. T.F.-W. was supported by a Cancer Research UK PhD Studentship. C.E.-G. and D.A.T. are supported by Cancer Research UK Programme grant C42109/A24757. H.G. is supported by a British Society of Haematology Early-Stage Research grant. A.P.C. is a recipient of a Medical Research Council Career Development Fellowship (MR/V010182/1). Copyright: {\textcopyright} 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.",

year = "2023",

month = oct,

day = "24",

doi = "10.1182/bloodadvances.2023009890",

language = "English",

volume = "7",

pages = "6035--6047",

journal = "Blood Advances",

issn = "2473-9529",

publisher = "American Society of Hematology",

number = "20",

}

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 2023, 'Uptake of long-chain fatty acids from the bone marrow suppresses CD8⁺ T-cell metabolism and function in multiple myeloma', Blood Advances, vol. 7, no. 20, pp. 6035-6047. https://doi.org/10.1182/bloodadvances.2023009890

TY - JOUR

T1 - Uptake of long-chain fatty acids from the bone marrow suppresses CD8+ T-cell metabolism and function in multiple myeloma

AU - Gudgeon, Nancy

AU - Giles, Hannah

AU - Bishop, Emma L

AU - Fulton-Ward, Taylor

AU - Escribano-Gonzalez, Cristina

AU - Munford, Haydn

AU - James-Bott, Anna

AU - Foster, Kane

AU - Karim, Farheen

AU - Jayawardana, Dedunu

AU - Mahmood, Ansar

AU - Cribbs, Adam P

AU - Tennant, Daniel A

AU - Basu, Supratik

AU - Pratt, Guy

AU - Dimeloe, Sarah

N1 - Acknowledgments: The authors gratefully acknowledge the contribution to this study made by the University of Birmingham’s Human Biomaterials Resource Centre, which was set up through the Birmingham Science City, Experimental Medicine Network of Excellence Project. This work was funded by Leukaemia UK John Goldman Fellowship and Blood Cancer UK Project grant 21007 (S.D.), which also supported N.G. and H.M. T.F.-W. was supported by a Cancer Research UK PhD Studentship. C.E.-G. and D.A.T. are supported by Cancer Research UK Programme grant C42109/A24757. H.G. is supported by a British Society of Haematology Early-Stage Research grant. A.P.C. is a recipient of a Medical Research Council Career Development Fellowship (MR/V010182/1). Copyright: © 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.

PY - 2023/10/24

Y1 - 2023/10/24

N2 - 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.

AB - 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.

U2 - 10.1182/bloodadvances.2023009890

DO - 10.1182/bloodadvances.2023009890

M3 - Article

C2 - 37276076

SN - 2473-9529

VL - 7

SP - 6035

EP - 6047

JO - Blood Advances

JF - Blood Advances

IS - 20

ER -