Increased lipid metabolism impairs NK cell function and mediates adaptation to the lymphoma environment

Takumi Kobayashi, Pui Yeng Lam, Hui Jiang, Karolina Bednarska, Renee Gloury, Valentine Murigneux, Joshua Tay, Nicolas Jacquelot, Rui Li, Zewen Kelvin Tuong, Graham R. Leggatt, Maher K. Gandhi, Michelle M. Hill, Gabrielle T. Belz, Shyuan Ngo, Axel Kallies, Stephen R. Mattarollo*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

29 Citations (Scopus)

Abstract

Natural killer (NK) cells play critical roles in protection against hematological malignancies but can acquire a dysfunctional state, which limits antitumor immunity. However, the underlying reasons for this impaired NK cell function remain to be uncovered. We found that NK cells in aggressive B-cell lymphoma underwent substantial transcriptional reprogramming associated with increased lipid metabolism, including elevated expression of the transcriptional regulator peroxisome activator receptor-γ (PPAR-γ). Exposure to fatty acids in the lymphoma environment potently suppressed NK cell effector response and cellular metabolism. NK cells from both diffuse large B-cell lymphoma patients and Em-myc B-cell lymphoma-bearing mice displayed reduced interferon-γ (IFN-γ) production. Activation of PPAR-γ partially restored mitochondrialmembrane potential and IFN-γ production.Overall, our data indicate that increased lipid metabolism, while impairing their function, is a functional adaptation of NK cells to the fatty-acid rich lymphoma environment.

Original languageEnglish
Pages (from-to)3004-3017
Number of pages14
JournalBlood
Volume136
Issue number26
DOIs
Publication statusPublished - 24 Dec 2020
Externally publishedYes

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