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
Article Link: Click here
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.