NF-κB-inducing kinase maintains T cell metabolic fitness in antitumor immunity

Abstract

Metabolic reprograming towards aerobic glycolysis is a pivotal mechanism shaping immune responses. Here we show deficiency in NF-κB-inducing kinase (NIK) impairs glycolysis induction, rendering CD8 + effector T cells hypofunctional in tumor microenvironment. Conversely, ectopic expression of NIK promotes CD8 + T cell metabolism and effector function, thereby profoundly enhancing antitumor immunity and improving the efficacy of T cell adoptive therapy. NIK regulates T cell metabolism via an NF-κB-independent mechanism that involves stabilization of hexokinase 2 (HK2), a rate-limiting enzyme of the glycolytic pathway. NIK prevents autophagic degradation of HK2 through controlling cellular ROS levels, which in turn involves modulation of glucose-6-phosphate dehydrogenase (G6PD), an enzyme mediating production of the antioxidant NADPH. We show that the G6PD-NADPH redox system is important for HK2 stability and metabolism in activated T cells. These findings establish NIK as a pivotal regulator of T cell metabolism and highlight a posttranslational mechanism of metabolic regulation.

Interleukins in cancer: from biology to therapy

“…Cancer cells can induce metabolic reprogramming of immune cells in the TME and systemic changes in metab olism, which can induce the transition from proinflam matory to immunosuppressive responses 53 . A glycolytic switch in effector T cells dependent on NFκBinducing kinase (NIK) signalling was recently demonstrated as pivotal for antitumour immunity in a mouse melanoma model 138 . The accumulation of glycolysisderived lactate in the TME can increase oxidative phosphorylation and together with IL4 induces antiinflammatory repro gramming (involving M2 polarization of macrophages and secretion of IL10 and TGFβ) 53 .…”

Aberrant accumulation of NIK promotes tumorigenicity by dysregulating post-translational modifications in breast cancer

“…In contrast, inactivating NIK mutations have been shown to cause immunodeficiency, such as decreased numbers of mature B cells and T cells their functional impairment 47 . NIK plays an important role in antitumor immunity by regulating metabolism in cytotoxic CD8 + T cells 48 . Therefore, it is necessary to develop NIK inhibitors through further comprehension of the reciprocal NIK functions to avoid interfering with the homeostatic role that NIK plays in the body.…”

Metabolic and Mitochondrial Functioning in Chimeric Antigen Receptor (CAR)—T Cells

“…G6P can be dehydrogenated in the pentose phosphate pathway (PPP) to produce NADH for use as both a reducing agent in the synthesis of fatty acids and a cofactor in the synthesis of nucleotides for DNA replication. Dwindling glycolysis capacity by blocking HK2 favours T cell expansion [58], without affecting CD8 + T cell activation through TCR-CD28 stimulation [58,87]. HK2 knock-out causes a severe antitumour activity in CD8 + T cells by overexpressing PD-1 and Tim3 [87].…”

“…Dwindling glycolysis capacity by blocking HK2 favours T cell expansion [58], without affecting CD8 + T cell activation through TCR-CD28 stimulation [58,87]. HK2 knock-out causes a severe antitumour activity in CD8 + T cells by overexpressing PD-1 and Tim3 [87]. Interestingly, HK2 deletion seems to be dispensable for CD4 + T cell responses against viral infection [85,88] but not for CD8 + responses [87].…”

“…HK2 knock-out causes a severe antitumour activity in CD8 + T cells by overexpressing PD-1 and Tim3 [87]. Interestingly, HK2 deletion seems to be dispensable for CD4 + T cell responses against viral infection [85,88] but not for CD8 + responses [87]. However, the long-term efficacy of T cells that no longer possess a key metabolic gene is difficult to predict.…”