Increased lipid metabolism impairs NK cell function and mediates adaptation to the lymphoma environment
T 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 T. Ngo, Axel Kallies, Stephen R. Mattarollo
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.