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

Lymphoma
21/08/2020

Blood. 2020 Aug 20:blood.2020005602. doi: 10.1182/blood.2020005602. Online ahead of print.

ABSTRACT

NK cells play critical roles in protection against haematological malignancies but can acquire a dysfunctional state, which limits anti-tumour 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 PPAR-g. 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 IFN-g production. Activation of PPAR-g partially restored mitochondrial membrane potential and IFN-g 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.