Lipid Microenvironment With B-Cell Lymphoma and Natural Killer Cell Function

A study highlights a possible relationship between lipid metabolism and natural killer (NK) cell function in aggressive B-cell lymphomas, with a lipid-rich lymphoma microenvironment linked to lower NK cell function. Findings of the study were reported in the journal Blood.

“Aggressive B-cell lymphoma and other [hematological] malignancies dampen NK cell function. However, the mechanisms that control NK cell homeostasis or function in the lymphoma environment remain poorly understood,” explained the researchers in their report.

In this study, researchers studied gene expression in NK cells derived from humans with diffuse large B-cell lymphoma (DBLCL) and from B-cell lymphoma-containing Em-myc mice, in addition to peripheral blood mononuclear cells derived from healthy human donors.

Cells were treated with a mixture of fatty acids, including palmitic, oleic, and linoleic acids, and gene expression and metabolic analyses were performed. Rosiglitazone was also given to mice for peroxisome activator receptor-g (PPAR-g) activation in order to ascertain any impact on NK cell function.

The researchers discovered that aggressive B-cell lymphoma was associated with transcriptional changes in NK cells related to enhanced lipid metabolism. This included an upregulation of expression of PPAR-g.

The researchers also found that several fatty acids were present at high levels in the plasma of mice with lymphoma, in comparison with other metabolites that were not present in unusual amounts. They then treated NK cells with multiple fatty acids and observed that palmitic acid impacted interferon-g (IFN-g) production, in addition to other effects.

NK effector response and overall metabolism were both inhibited in the B-cell lymphoma microenvironment. NK cells from both humans with DLBCL and mice with lymphoma had lower levels of IFN-g. Treatment of NK cells with rosiglitazone, through activation of PPAR-g, aided in recovery of IFN-g production.

The researchers concluded that fatty acids associated with B-cell lymphoma may act to suppress cytokine activity in NK cells. They also determined that the lipid-associated stress imparted by the B-cell lymphoma microenvironment leads to an increase in lipid metabolism in NK cells.

The researchers also indicated that other metabolic changes may occur with lymphoma that could influence NK cell metabolism, and they suggested that further research be undertaken to more fully understand metabolic alterations that may occur with lymphoma.

“Overall, our data [suggest] that manipulating cellular metabolism of NK cells constitutes a new therapeutic avenue that could contribute to the treatment of B cell lymphoma,” the researchers stated in their report.

Reference

Kobayashi T, Lam PY, Jiang H, et al. Increased lipid metabolism impairs NK cell function and mediates adaptation to the lymphoma environment. Blood. Published online August 20, 2020. doi:10.1182/blood.2020005602