Metabolic Adaptation to Lymphoma Suppresses NK-Cell Antitumor Function

Immune surveillance by natural killer (NK) cells can confer antitumor immunity, but NK-cell function can be impaired in cancer for reasons that remain unknown. In an investigation of NK-cell effector function in diffuse large B-cell lymphoma (DLBCL), Kobayashi and colleagues first found that patient-derived NK cells had normal maturation and cytotoxic activity but reduced degranulation upon recognition of target cells and decreased production of IFNγ following stimulation. Eμ-MYC mice, which model aggressive B-cell lymphoma, had fewer NK cells in the bone marrow and spleen than healthy mice, and they had more fully mature CD11b⁺ NK cells. The NK cells from Eμ-MYC mice produced less IFNγ in response to stimulation with IL12 and IL18 and reduced IFNγ and Granzyme B production in response to α-galactosylceramide (an inducer of NK-cell activation). Further, NK cells from Eμ-MYC mice exhibited upregulation of Tigit and Lag3, which encode inhibitory receptors, and Il10, which encodes an immunosuppressive cytokine, implying that these NK cells had an exhausted phenotype. In agreement with this notion, gene set enrichment analysis showed that the gene-ontology terms “negative regulation of immune system process” and “response to lipid” were enriched in Eμ-MYC NK cells; additionally, the lipid-metabolism genes Cd36, Fabp4/5, and Pparg were upregulated. Correspondingly, metabolic profiling revealed that Eμ-MYC mouse NK cells and NK cells from patients with DLBCL had higher levels of neutral lipids, and Eμ-MYC mouse NK cells had reduced mitochondrial mass and membrane potential. Eμ-MYC mice had higher plasma concentrations of multiple fatty acids (FA), and treatment of NK cells with either of two saturated FAs (palmitic acid or steric acid) reduced expression of IFNγ, TNF, and Granzyme B without reducing cell viability. Specifically, palmitic acid impaired cytokine-induced activation of NK-cell metabolism, and adaptation of NK-cell metabolism to lipid-rich lymphomas was mediated by PPARγ and FABP4/5, which aided mitochondrial metabolism and IFNγ production. In summary, this work demonstrates how lymphoma influences NK-cell metabolism and function to suppress NK-cell mediated antitumor immunity.

Kobayashi T, Lam PY, Jiang H, Bednarska K, Gloury RE, Murigneux V, Tay J, et al. Increased lipid metabolism impairs NK cell function and mediates adaptation to the lymphoma environment. Blood 2020 Aug 20 [Epub ahead of print].

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