WASHINGTON: Researchers at the University of Texas MD Anderson Cancer Center have discovered that a protein called NF-kappa B-induc kinase (NIK) is essential for the shift in metabolic activity that occurs through cell activity T, making it a critical feature in the regulation of the tumor immune response.
The preclinical research, published today in Nature Immunology, suggests that increasing NIK activity in T cells may be a promising strategy to increase the effectiveness of immunotherapy, including breast-cell therapies. adoption and prevention of protection check.
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 the regulation of the redox cellular pathway,” the corresponding author Shao-Cong Sun, Ph.D., professor of Psychology.
“From a therapeutic perspective, we were able to improve the efficacy of adoptive T cell therapies in preclinical models by overexpressing NIK in these cells,” Sun said.
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.
In melanoma models, NIK loss resulted in increased 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. Interestingly, find by adding more NIK to the cells, you can further increase the levels of HK2 and make glycolysis more active, Sun said.
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.
The preclinical research, published today in Nature Immunology, suggests that increasing NIK activity in T cells may be a promising strategy to increase the effectiveness of immunotherapy, including breast-cell therapies. adoption and prevention of protection check.
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 the regulation of the redox cellular pathway,” the corresponding author Shao-Cong Sun, Ph.D., professor of Psychology.
“From a therapeutic perspective, we were able to improve the efficacy of adoptive T cell therapies in preclinical models by overexpressing NIK in these cells,” Sun said.
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.
In melanoma models, NIK loss resulted in increased 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. Interestingly, find by adding more NIK to the cells, you can further increase the levels of HK2 and make glycolysis more active, Sun said.
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.