In this issue of Blood, Kobayashi and colleagues detail how the change in the transcriptional program of natural killer (NK) cells toward one of lipid metabolism with immunosuppressive tendencies makes them less effective killers in the lymphoma tumor environment.1 

Work dating back to 1974 noted the suppressive role of fatty acids (FAs) on lymphocyte function.2  The current study identifies features of the mature B-cell lymphoma environment rich in FAs that impair NK cell function. Michelet and colleagues showed that, in obese mice, lipids can accumulate within NK cells and impede the cytotoxic machinery.3  Obesity is associated with an increased risk of cancer and immune dysfunction. For these obese mice, FA treatment did not impair the ability of NK cells to recognize tumors, just the ability to kill them: Increased lipid metabolism was associated with decreased cytotoxicity. When FA accumulation was blocked and mitochondrial glycolysis was restored, so was killing efficiency. This observation suggests that blocking either lipid uptake or lipid metabolism by NK cells could enhance their killing ability and provide a potential adjuvant therapy to cancer treatment.

The lymphoma microenvironment is enriched in FA. Therefore, Kobayashi and colleagues evaluated lipid-mediated NK cell dysfunction in lymphoma by examining NK cells from human diffuse large B-cell lymphoma (DLBCL) patients and Eμ-myc B-cell mice. NK cells go through a series of coordinated steps to kill, providing antitumor activity through the secretion of inflammatory cytokines, such as interferon-γ (IFN-γ), production, and release of cytotoxic granule contents (perforin and granzyme). To accelerate the phases of killing, changes of cellular metabolism occur to support growth proliferation and cellular functions.4  These steps and functions are the hallmark of harnessing the immune system for effective tumor surveillance. However, immune cell impairment can be driven by deprivation of nutrients or increase of toxic metabolites in the tumor environment.

In this study, the authors showed that NK cells in human DLBCL patient-derived lymphoma cells displayed normal distribution of peripheral blood NK cells, that is, CD56bright (immature cytokine-producing cells) and CD56dim (mature cytotoxic) NK cells. Strikingly, the lymphoma-derived NK cells had lower IFN-γ expression and less CD107a degranulation pointing to some functional impairment. In the Eμ-myc mouse model, the NK cells were reduced in number in bone marrow and spleen with impaired IFN-γ production. RNA sequencing of the healthy and Eμ-myc mice revealed no differential expression in IFN-γ, suggesting the reduced production was due to posttranslational modifications and not to an inherent NK cell abnormality. Analysis of the lymphoma NK cell transcriptome identified upregulation in inhibitory receptors Tigit and lag3 as well as Il10, pointing toward a “negative regulation of immune system process” and upregulation of critical regulators of lipid metabolism, such as Pparg. In addition, both mouse and human lymphoma cells exhibited marked increased neutral lipid levels.1  Polyunsaturated FAs, such as linoleic acid and docosahexaenoic acid, have been demonstrated to blunt the lipopolysaccharide inflammatory response in macrophages, increase the secretion of interleukin-10 (IL-10), and impair NF-κB by activating peroxisome activator 31 receptor-γ (PPAR-γ) along with impairment of IL-2 production and T-cell proliferation.5-8  Niavarani et al showed in a mouse tumor model of melanoma, breast, and colorectal cancer that surgical stress increased lipid content in NK cells leading to impairment in cell cytotoxicity and tumor control.9  In the Kobayashi study, treatment of the NK cells with PPAR-γ agonist rosiglitazone partially restored functional NK cells. This contrasts with what is seen in the obesity model in which increase in FA alone is detrimental to NK cell function. In the context of mature B-cell lymphoma microenvironment, lipid metabolism is augmented and may account for differences in NK function compared with obesity. Furthermore, other nutrient-based cellular processes could be affected by lipid metabolism as well. For example, the mammalian target of rapamycin (mTOR) pathway and glycolysis are essential to activate NK cell cytotoxicity.3  Kobayashi and colleagues show that in mature B-cell lymphoma NK cells mTOR signaling is decreased with decreased downstream phosphorylation of S6.

In the hypermetabolic environment of mature B-cell lymphoma, a “fatty meal” distracts NK cells from effective cancer immune responses. Manipulating FA/NK cell interactions therefore represents a novel immunotherapeutic strategy. More studies are needed to measure the effect of increased metabolism on activating receptors and detailed end-stage NK cell maturation to ascertain how the increased lipid metabolism can be regulated with a druggable target.

Conflict-of-interest disclosure: The author serves on the advisory board for Takeda, Grifols, and Horizon.

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