Elevating NIK Levels May Enhance Adoptive T Cell Therapies

Researchers at The University of Texas have discovered that a protein called NF-kappa B-inducing kinase (NIK) is essential for the shift in metabolic activity that occurs with T cell activation, making it a critical factor in regulating the anti-tumor immune response. Their study was published today in Nature Immunology. 

"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," said corresponding author Shao-Cong Sun. "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."

With the knowledge that the NIK protein functions downstream of many of these costimulatory molecules, the researchers sought to better understand its role in regulating T cell function. In melanoma models, NIK loss resulted in an increased tumor burden and fewer tumor-infiltrating T cells, suggesting NIK plays a crucial role in anti-tumor immunity and T cell survival.

Further experiments revealed that NIK is essential for the metabolic reprogramming in activated T cells through its control of the cellular redox system. Increased metabolism can lead to elevated levels of reactive oxygen species (ROS), which can damage the cell and stimulate protein degradation. The researchers discovered that NIK maintains the NADPH redox system, which in turn leads to the stabilization of the HK2 protein—a rate-limiting enzyme within the glycolysis pathway.

"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 adding more NIK to the cells, you can further increase the levels of HK2 and make glycolysis more active."