Researchers at the University of Texas MD Anderson Cancer Center found that a protein called NF-κB-inducible kinase (NIK) is essential for changes in metabolic activity caused by T cell activation, making it a regulator of T cell anti-tumor activity Key factors. Preclinical studies published in the journal Nature Immunology indicate that increasing the activity of NIK in T cells may be a promising strategy for enhancing the effectiveness of immunotherapy (including T cell transplantation and immune checkpoint blockade).
In preclinical melanoma models, the researchers evaluated melanoma-specific T cells that have been engineered to express higher levels of NIK. Compared with the control group, these T cells showed stronger tumor killing ability and improved survival rate, indicating that increasing NIK activity can improve the effectiveness of T cell therapy.
“NIK is a new type of T cell metabolism regulator, and its role is very unique. From a biological point of view, NIK activity stabilizes the HK2 glycolytic enzyme by regulating the redox pathway of the cell,” said corresponding author Dr. Shao-Cong Sun “From a therapeutic point of view, we can improve the efficacy of adoptive T cell therapy in preclinical models by overexpressing NIK in these cells.
Sun explained that T cells usually exist in a relatively quiet state, with low energy requirements and very little cell division. However, after recognizing the antigen, T cells begin to expand and activate glycolytic metabolic pathways to meet the increased energy demand for performing their immune functions.
This metabolic change is strictly regulated by immune checkpoint proteins (such as CTLA-4 and PD-1), which can inhibit T cell metabolism. Therefore, immune checkpoint inhibitors can enhance the anti-tumor activity of T cells by promoting metabolism. In addition, after being activated, T cells begin to produce proteins called costimulatory molecules, which can stimulate metabolism and immune responses.
Researchers know that the NIK protein acts downstream of many of these costimulatory molecules, and therefore seek to better understand its role in regulating T cell function. In the melanoma model, the loss of NIK leads to an increase in tumor burden and a decrease in tumor infiltrating T cells, which indicates that NIK plays a vital role in anti-tumor immunity and T cell survival.
Further experiments show that NIK is essential for activating metabolic reprogramming in T cells by controlling the cellular redox system. Increased metabolism leads to increased levels of reactive oxygen species (ROS), which damage cells and stimulate protein degradation. The researchers found that NIK maintains the NADPH redox system, which is an important antioxidant mechanism that reduces ROS accumulation. This in turn leads to the stability of HK2 protein, which is the rate-limiting enzyme in the glycolysis pathway.
Sun said: “Our findings indicate that without NIK, HK2 protein will be unstable and will continue to degrade. You need NIK to maintain the level of HK2 in T cells. Interestingly, we found that more NIK is added to the cells. It can further increase the level of HK2 and make glycolysis more active.” In the future, researchers hope to explore other treatments, such as targeted therapies that can manipulate NIK activity in conjunction with other immunotherapies (including immune checkpoint inhibitors).
