Regulating the activity of the protein called NF-kappa B-inducing kinase (NIK) is emerging as a new and potentially important way to enhance certain immuno-oncology therapies.
In preclinical experiments, researchers at MD Anderson Cancer Center (working with Genentech, Precision for Medicine, Korea’s Busan National University and Seoul National University) established NIK as a pivotal regulator of T cell metabolism and thus a critical factor in regulating the anti-tumor immune response.
As corresponding author Shao-Cong Sun, Ph.D., professor of immunology, told BioSpace, “Our work suggests that pharmacological agents that stabilize NIK may be effective for promoting antitumor T cell functions.”
The research, just-published in Nature Immunotherapy, suggests that elevating NIK activity could be particularly beneficial as a therapy when used alongside adoptive cellular therapies or immune checkpoint inhibitors.
Specifically, Sun and colleagues reported that “deficiency in NF-κB-inducing kinase (NIK) impairs glycolysis induction, rendering CD8+ effector T cells hypofunctional in the tumor microenvironment. Conversely, the abnormal expression of NIK enhances CD8+ T cell metabolisms and effector function, profoundly enhancing antitumor immunity and improving the efficacy of T cell adoptive therapy.”
Elaborating in a statement, Sun said, “NIK is a novel regulator of T cell metabolism that works in a very unique manner. Biologically, NIK activity stabilizes the HK2 glycolytic enzyme through regulating the cellular redox pathway. From the therapeutic point of view, we were able to improve the efficacy of adoptive T cell therapies in preclinical models by overexpressing NIK in those cells.”
Sun and colleagues evaluated melanoma-specific T cells that were engineered to express higher levels of NIK. They found these T cells were more potent tumor killers than the control T cells, and that they also survived longer. Those results suggest that increasing NIK activity may make adoptive T cell therapies more effective.
T cells generally exist in a relatively quiet state with low energy demands and little cell division, Sun explained. However, upon recognizing an antigen, T cells begin expanding and activate the glycolysis metabolic pathway to meet the increased energy demands of carrying out their immune function.
This metabolic shift is closely regulated by immune checkpoint proteins, such as CTLA-4 and PD-1, which repress T cell metabolism. Thus, immune checkpoint inhibitors can reinvigorate T cell anti-tumor activity by boosting metabolism.
The T cells also begin producing proteins called costimulatory molecules after they become activated. Those costimulatory molecules stimulate metabolism and the immune response.
The NIK protein functions downstream of the costimulatory molecules. When the NIK protein function is lost, the tumor burden increases, and the number of tumor-infiltrating T cells decreases. This suggests NIK is pivotal to anti-tumor immunity and T cell survival.
Subsequent experiments showed that NIK controls the cellular redox system and therefore is vital to the metabolic reprogramming of activated T cells. Increasing cells’ metabolism can trigger the increase of reactive oxygen species that, in turn, may damage cells and lead to protein degradation.
Because NIK maintains the NADPH redox system (an important antioxidant mechanism that reduces the accumulation of reactive oxygen species), NIK helps stabilize the HK2 protein, which is a rate-limiting enzyme in the glycolysis pathway.
“Inducing an NIK deficiency had no effect on mRNA expression of glycolysis-regulatory genes or glucose uptake,” the paper noted. It did, however, promote lysosomal localization of HK2.
“Our findings suggest that without NIK, the HK2 protein is not stable and is constantly being degraded. You need NIK to maintain HK2 levels in T cells,” Sun said. “Interestingly, we found that by adding more NIK to the cells, you can further increase the levels of HK2 and make glycolysis more active.”
Moving forward, Sun told BioSpace, “We will further examine the mechanism by which NIK regulates the cellular redox system and metabolism. We also will study how the NIK signaling axis prevents T cell exhaustion in the tumor microenvironment.
“To further evaluate NIK as a potential target for cancer immunotherapy, we will employ the mouse model of a chimeric antigen receptor (CAR) T cell therapy approach to test whether ectopic expression of NIK improves the therapeutic efficacy.”
Additional therapeutic approaches, including targeted therapies to manipulate NIK activity in concert with other immunotherapies, also may be studied.
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