Sweet Killers: NK Cells Need Glycolysis to Kill Tumors
Authors: Batya Isaacson, Ofer Mandelboim
Journal: Cell Metabolism (2018)

Natural killer (NK) cells are cytotoxic innate lymphocytes that play a major role in the immune battle against cancer. In this issue of Cell Metabolism, Cong et al., 2018Cong J. Wang X. Zheng X. Wang D. Fu B. Sun R. Tian Z. Wei H. Dysfunction of natural killer cells by FBP1-induced inhibition of glycolysis during lung cancer progression.Cell Metab. 2018; 28 (this issue): 243-255Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar demonstrate that progressing tumors reduce NK cell glycolytic capacity, which leads to reduced cytotoxicity and an overall dysfunctional NK phenotype. Natural killer (NK) cells are cytotoxic innate lymphocytes that play a major role in the immune battle against cancer. In this issue of Cell Metabolism, Cong et al., 2018Cong J. Wang X. Zheng X. Wang D. Fu B. Sun R. Tian Z. Wei H. Dysfunction of natural killer cells by FBP1-induced inhibition of glycolysis during lung cancer progression.Cell Metab. 2018; 28 (this issue): 243-255Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar demonstrate that progressing tumors reduce NK cell glycolytic capacity, which leads to reduced cytotoxicity and an overall dysfunctional NK phenotype. First discovered in the late 1960s and named for their ability to kill tumors without prior stimulation, natural killer (NK) cells are innate immune lymphocytes that play an important role in the immune defense against various threats, one of which is cancer. NK cells can control tumor development and progression by directly killing malignantly transformed cells through the secretion of cytotoxic molecules; in addition, they coordinate a broad immune response aimed at the tumor through the secretion of various cytokines (Morvan and Lanier, 2016Morvan M.G. Lanier L.L. NK cells and cancer: you can teach innate cells new tricks.Nat. Rev. Cancer. 2016; 16: 7-19Crossref PubMed Scopus (697) Google Scholar). These functions are energetically expensive, and thus metabolic reprograming of NK cells is essential for their activity. Indeed, activated NK cells were shown to shift their metabolism from fatty acid oxidation to glycolysis and oxidative phosphorylation (Assmann et al., 2017Assmann N. O'Brien K.L. Donnelly R.P. Dyck L. Zaiatz-Bittencourt V. Loftus R.M. Heinrich P. Oefner P.J. Lynch L. Gardiner C.M. et al.Srebp-controlled glucose metabolism is essential for NK cell functional responses.Nat. Immunol. 2017; 18: 1197-1206Crossref PubMed Scopus (182) Google Scholar). Although unable to infiltrate into tumors, NK cells play a crucial role in tumor progression and even metastasis formation (Morvan and Lanier, 2016Morvan M.G. Lanier L.L. NK cells and cancer: you can teach innate cells new tricks.Nat. Rev. Cancer. 2016; 16: 7-19Crossref PubMed Scopus (697) Google Scholar, Glasner et al., 2018Glasner A. Levi A. Enk J. Isaacson B. Viukov S. Orlanski S. Scope A. Neuman T. Enk C.D. Hanna J.H. et al.NKp46 receptor-mediated interferon-γ production by natural killer cells increases fibronectin 1 to alter tumor architecture and control metastasis.Immunity. 2018; 48: 107-119.e4Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). Lacking rearrangeable receptors, NK cells express an array of inhibitory and activating receptors that bind various pathogen and tumor ligands, some of which are still unknown. This engagement results in the secretion of cytotoxic molecules and inflammatory cytokines that can change the course of tumor development, even from the tumor margins. Tumor cells, on the other hand, have developed various mechanisms to "con" NK cells and evade elimination. Moreover, tumor cells can secrete various factors that manipulate NK cells to become non-cytotoxic tumor promoters that enable tumor progression through the secretion of molecules such as vascular endothelial growth factor (VEGF) (Levi et al., 2015Levi I. Amsalem H. Nissan A. Darash-Yahana M. Peretz T. Mandelboim O. Rachmilewitz J. Characterization of tumor infiltrating natural killer cell subset.Oncotarget. 2015; 6: 13835-13843Crossref PubMed Scopus (95) Google Scholar). The immune system responds intensely to tumors; in fact, immune cells were identified within tumors as early as the 19th century (Virchow, 1863Virchow R. Cellular Pathology. As Based upon Physiological and Pathological Histology. J.B. Lippincott, 1863Google Scholar). The tumor microenvironment has been shown to have a strong effect on the immune cells in its vicinity (Gajewski et al., 2013Gajewski T.F. Schreiber H. Fu Y.X. Innate and adaptive immune cells in the tumor microenvironment.Nat. Immunol. 2013; 14: 1014-1022Crossref PubMed Scopus (2374) Google Scholar). Immune cells localized at the tumor site show an altered phenotype, including upregulation of exhaustion markers, reduced cytotoxicity, and overall dysfunction. In this issue of Cell Metabolism, Cong et al., 2018Cong J. Wang X. Zheng X. Wang D. Fu B. Sun R. Tian Z. Wei H. Dysfunction of natural killer cells by FBP1-induced inhibition of glycolysis during lung cancer progression.Cell Metab. 2018; 28 (this issue): 243-255Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar meticulously demonstrate how, by manipulation of NK cell metabolism, KRAS-driven tumors can cause defective NK cell function to evade immune elimination. Since NK cells have been shown to play a role in tumor surveillance, accumulate around tumors, and have a strong anti-tumor effect (Morvan and Lanier, 2016Morvan M.G. Lanier L.L. NK cells and cancer: you can teach innate cells new tricks.Nat. Rev. Cancer. 2016; 16: 7-19Crossref PubMed Scopus (697) Google Scholar), Cong et al. checked the role NK cells play in different stages of KRAS-driven lung cancer by depleting NK cells in the initiation, promotion, and progression of the tumor (Figure 1). The authors found that NK cells played a major role specifically in the initiation stage but failed to hinder lung cancer progression at later stages. The authors noticed that NK cells at later tumor stages were found in lower numbers, which kept decreasing as the tumor progressed. Furthermore, these low-numbered NK cells in the tumor microenvironment showed a dysfunctional phenotype, which included reduced secretion of cytotoxic molecules such as Perforin and Granzyme B and inflammatory cytokines such as IFNγ and TNFα, and elevated expression of inhibitory receptors (Figure 1). Transcriptome analysis of tumor-associated NK cells at different stages found a 69-fold increase in fructose-1,6-bisphosphatase (FBP1), a key enzyme in gluconeogenesis. Its level of expression was correlated with the KRAS-driven tumor progression, and its upregulation was mediated by TGFβ, an immunosuppressive cytokine abundantly found in the tumor microenvironment (Flavell et al., 2010Flavell R.A. Sanjabi S. Wrzesinski S.H. Licona-Limon P. The polarization of immune cells in the tumour environment by TGFbeta.Nat. Rev. Immunol. 2010; 10: 554-567Crossref PubMed Scopus (666) Google Scholar) (Figure 1). Glycolysis (the production of energy from glucose) and gluconeogenesis (the generation of glucose from non-carbohydrate precursors) are opposing in nature, tightly regulated, and almost mutually exclusive (Pilkis and Granner, 1992Pilkis S.J. Granner D.K. Molecular physiology of the regulation of hepatic gluconeogenesis and glycolysis.Annu. Rev. Physiol. 1992; 54: 885-909Crossref PubMed Scopus (704) Google Scholar). FBP1 is a key and rate-limiting enzyme in gluconeogenesis, and its elevated expression in tumor-associated NK cells resulted in decreased glycolytic capacity. Inhibition of FBP1 was sufficient to restore glycolysis. As a result, tumor-associated NK cells' cytotoxicity and viability were increased. This reversal was only partial in NK cells derived from more advanced, later-stage tumors. The findings of Cong et al., 2018Cong J. Wang X. Zheng X. Wang D. Fu B. Sun R. Tian Z. Wei H. Dysfunction of natural killer cells by FBP1-induced inhibition of glycolysis during lung cancer progression.Cell Metab. 2018; 28 (this issue): 243-255Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar bring to light a novel mechanism employed by tumors to escape elimination by NK cells, emphasizing the important part NK cells play in the battle against the tumor. In T cells, it was shown that CD28 engagement, an essential signal for full activation, regulates glucose metabolism (Frauwirth et al., 2002Frauwirth K.A. Riley J.L. Harris M.H. Parry R.V. Rathmell J.C. Plas D.R. Elstrom R.L. June C.H. Thompson C.B. The CD28 signaling pathway regulates glucose metabolism.Immunity. 2002; 16: 769-777Abstract Full Text Full Text PDF PubMed Scopus (1005) Google Scholar). As NK cells can kill without prior stimulation, the exact mechanism by which glycolysis affects NK cell cytotoxicity in such a dramatic manner remains to be elucidated. Although beautifully shown in mouse KRAS-driven lung cancer, it is unclear whether FBP1 induction of dysfunctional NK cell cytotoxicity occurs in other types of lung cancer or in other solid tumors in general. More importantly, this tumor-induced metabolic inhibition of cytotoxic capacity has yet to be demonstrated in humans. This question is important to understand whether clinical use of FBP1 inhibitors may yield positive results in KRAS-driven cancer patients. It is becoming clearer that effector cell function and metabolism go hand in hand, making it worthwhile and important to better understand how one affects the other and how various pathologies interfere with one or the other. In the age where tumors develop resistance to various biological drugs, cancer immunotherapy has shown astonishing results and promising potential, granting patients with aggressive malignancies an expanded lifespan and even complete remission. It is of immense importance to understand the different ways cancer can manipulate the immune system so that therapies may be developed to restore its capacity to fully eradicate tumor cells. This work was supported by the Israel Science Foundation and the ICRF professorship grant to O.M. Dysfunction of Natural Killer Cells by FBP1-Induced Inhibition of Glycolysis during Lung Cancer ProgressionCong et al.Cell MetabolismJuly 19, 2018In BriefCong et al. demonstrate that NK cells lose their antitumor effect gradually and ultimately evolve into a dysfunctional state during tumor development. The tumor microenvironment disables NK cells by weakening their glycolytic metabolism, thus promoting tumor immune escape; remarkably, FBP1 acts as a key molecule in this process. Full-Text PDF Open Archive