Increased lipid metabolism impairs NK cell function and mediates adaptation to the lymphoma environment
Takumi Kobayashi, Pui Yeng Lam, Hui Jiang, Karolina Bednarska, Renee Elyse 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
Blood | AMER SOC HEMATOLOGY | Published : 2020
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 reduc..View full abstract
Awarded by National Health and Medical Research Council
The authors acknowledge the excellent support from the Translational Research Institute core facility units and Walter and Eliza Hall Institute facilities, in particular, MS, flow cytometry, and biological resource facility. The authors also acknowledge the experimental support for biochemical analysis from UQ Veterinary Laboratory Service and thank Thomas Stoll and the QIMR Berghofer Metabolomics Facility for technical support including the MS analysis of free fatty acids. In addition, the authors thank Dominique Dubal, Nikolai Gorbunov, Dale David Orr Martin, Fernando Souza-Fonseca-Guimaraes, Rebecca Delconte, Nicholas Huntington, and Dirk Brenner for scientific advice. This work was funded by National Health and Medical Research Council grant 1044355 (S.R.M.), and fellowships 1061429 (S.R.M.), and 1139607 (A.K.), the Sylvia and Charles Viertel Foundation fellowship (A.K.), and a generous donation from Mr. and Mrs. Pegler (S.R.M.).