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

Authors:

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

Details:

Blood, Volume 136, Issue 26, 2020-12-24

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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 Eµ-myc B-cell lymphoma-bearing mice displayed reduced interferon-γ (IFN-γ) production. Activation of PPAR-γ partially restored mitochondrial membrane 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.