Metabolic regulation of NK cells in blood cancers: Lipid-rich environment in blood cancers is associated with metabolic and functional changes of NK cells

Abstract

Immunological responses suppress tumour development and are a major target of immunotherapies. Natural killer (NK) cells are highly effective at killing malignant cells and modulate other immune effectors, and therefore are a primary target of tumour-targeted monoclonal antibody (MAb) therapies.In haematological malignancies, optimal function of NK cells is essential for suppressing tumour growth and the success of immunotherapeutic regimens, such as rituximab, an anti-CD20 MAb therapy for B cell malignancies. Advanced stages or aggressive lymphomas are associated with functional defects of NK cells, which leads to suboptimal responses of immunotherapeutic effects. However, the mechanisms by which lymphomas dampen NK cell function are largely unexplored, and understanding this process is critical for better designs and development of therapeutic strategies for lymphoma.Recent advances in immunological research uncovered the importance of cellular metabolism in determining functional fates of immune cells. Accumulating evidence also suggests that malignant cell metabolism does not only potentiate accelerated growth of tumours, but also has a significant impact on surrounding metabolic environments. Therefore, we hypothesized that blood cancers, which disseminate into lymphoid organs, cause a metabolic catastrophe in the critical immune niches Kobayashi T and Mattarollo SR. (2017). Natural killer cell metabolism. Mol immunol. 2017 Nov 24. Publications included in this thesis Contributions by others to the thesisNcr CreT/+ and Ncr CreT/+ Pparg fl/fl mice were provided by Belz G (WEHI). Immune cell sorting and PCR confirmation of Tg mouse genotype were conducted by Jacquelot N (WEHI) from Belz Lab. Eµ-myc and AML survival curves and tumour burdens were obtained by Lam PY Spleens derived from AT3 tumour-bearing mice were provided by Mazzieri R NK cell mitochondrial images were taken by Kobayashi T and Tay J LC-MS for quantifying plasma FA levels were conducted by Kobayashi T, Jiang H (Hill Lab, UQDI), and Hill M (UQDI/QIMR) RNA sequencing from the sample preparation to the sequencing was conducted by Gloury R and Kallies A (PDI). RNAseq data was analysed by Kobayashi T, Murigneux V, Tuong ZK.Glucose, lactate, cholesterol, TG quantification were conducted by UQ Veterinary Laboratory