Researchers discover proteins that are essential for T cell metabolism and immune response against tumors

Researchers at the University of Texas MD Anderson Cancer Center have found that a protein called NF-kappa B-induc kinase (NIK) is essential for the shift in metabolic activity that occurs with T cell activity, making it a critical feature in the management of the tumor-response response.

The preclinical research, published today in Psychology of nature, suggests that increased NIK activity in T cells may be a promising strategy to increase the efficacy of immunotherapy, including cellular therapies and immune check inhibition.

In a preclinical melanoma model, the researchers evaluated melanoma-specific T cells that were engineered to express higher levels of NIK. Compared with controls, these T cells showed stronger tumor killing abilities and better survival, suggesting that NIK activity may increase the effectiveness of adoptive T cell therapies.

NIK is a novel regulator of T cell metabolism that works in a unique way. Biologically, NIK activity forms the basis of the glycolytic enzyme HK2 through regulation of the redox cellular pathway. From a therapeutic point of view, we were able to improve the efficacy of adoptive T cell therapies in preclinical models by overexpressing NIK in these cells. “

Shao-Cong Sun, Ph.D., Professor of Immunology, Corresponding Author

T cells are usually in a relatively quiet state with low energy demands and very little cell division, Sun explained. However, when they recognize an antigen, T cells begin to expand and activate the glycolysis metabolic pathway to meet the increased energy demands in terms of performing the immune function.

This metabolic movement is closely regulated by immune check proteins, such as CTLA-4 and PD-1, which work to reverse T cell metabolism. Thus, immune point inhibitors can restore T-cell anti-tumor activity by stimulating metabolism. In addition, T cells begin to secrete proteins called costimulatory molecules after they are activated, which work to stimulate metabolism and the immune response.

Knowing that the NIK protein works downstream of many of these costimulatory molecules, the researchers sought to better understand its role in regulating T cell function. melanoma, loss of NIK caused more tumor burden and fewer tumor-infiltrating T cells, suggesting that NIK plays a critical role in tumor immunity and T cell survival.

Further experiments have shown that NIK is essential for metabolic remodeling in activated T cells through its control of the redox cell system. Increased metabolism can lead to high levels of reactive oxygen species (ROS), which can damage the cell and promote protein contamination.

The researchers found that NIK maintains the redox system of NADPH, an important antioxidant mechanism to reduce ROS accumulation. This in turn leads to the stability of the protein HK2, an enzyme that restricts levels within the glycolysis pathway.

“Our findings suggest that, without NIK, the HK2 protein is not stable, and is constantly depleted. You need to maintain NIK HK2 levels in T cells,” Sun said. “Interestingly, we found that by adding more NIK to the cells, you can increase HK2 levels and make glycolysis more active.”

As a potential therapeutic application, the researchers are currently working to evaluate chimney antigen receptor (CAR) T cells in the laboratory designed to overexpress NIK. In the future, they hope to explore other therapeutic approaches, such as targeted therapies that may treat NIK activity in combination with other immunotherapy modalities, including immunosuppressants.