Dysfunction of Natural Killer Cells by FBP1-Induced Inhibition of Glycolysis during Lung Cancer Progression

Abstract

Natural killer (NK) cells are effector lymphocytes with pivotal roles in the resistance against various tumors; dysfunction of NK cells often results in advanced tumor progression. Tumors develop in three stages comprising initiation, promotion, and progression, but little is known about the interrelationships between NK cells and tumor cells at different stages of tumor development. Here, we demonstrated that NK cells prevented tumor initiation potently but did not prevent tumor promotion or tumor progression in Kras-driven lung cancer. Moreover, loss of the antitumor effect in NK cells was closely associated with their dysfunctional state during tumor promotion and progression. Mechanistically, aberrant fructose-1,6-bisphosphatase (FBP1) expression in NK cells elicited their dysfunction by inhibiting glycolysis and impairing viability. Thus, our results show dynamic alterations of NK cells during tumor development and uncover a novel mechanism involved in NK cell dysfunction, suggesting potential directions for NK cell-based cancer immunotherapy involving FBP1 targeting.

NK cell metabolism

“…There is clear data from several groups that perturbing NK cell metabolism can inhibit NK cell functions . Inhibition of Oxphos strongly inhibits both cytotoxicity and IFNγ production.…”

“…Given the importance of NK cells in immunosurveillance and their potential use in immunotherapy treatment of cancer, the recent article of Cong et al is an exciting advance. It identifies fructose‐1,6‐biphosphatase 1 (FBP‐1) as an important regulator of glycolysis that becomes dysregulated during cancer and impacts on the anticancer activities of NK cells . FBP‐1 is a rate‐limiting enzyme in gluconeogenesis (the synthesis of glucose from noncarbohydrate carbon sources) and when expressed, it inhibits glycolysis.…”

“…Glycolysis in these NK cells was diminished as was immune function. Pharmacologically inhibition of FBP‐1 in these NK cells ex vivo restored glycolysis and key effector functions including cytotoxicity …”

“…There is clear data from several groups that perturbing NK cell metabolism can inhibit NK cell functions. 5,10,25,26,42,43 Inhibition of Oxphos strongly inhibits both cytotoxicity and IFN production. The data regarding inhibition of glycolysis are less clear and may reflect differences in experimental design including duration of stimulation, source of stimulation, concentration of drugs used, source of cells (e.g., priming during expansion), etc.…”

“…It identifies fructose-1,6biphosphatase 1 (FBP-1) as an important regulator of glycolysis that becomes dysregulated during cancer and impacts on the anticancer activities of NK cells. 42 FBP-1 is a rate-limiting enzyme in gluconeogenesis (the synthesis of glucose from noncarbohydrate carbon sources) and when expressed, it inhibits glycolysis. In their KRAS-driven lung cancer model, FBP-1 was not expressed in WT NK cells from the lung but was gradually induced in NK cells (possibly by TGF ) as the cancer developed.…”