Researchers identify a vital protein needed to regulate anti-tumor immune response

Scientists from The University of Texas MD Anderson Cancer Center have identified a protein known as NF-kappa B-inducing kinase (NIK). This protein plays a vital role in the shift in metabolic activity that happens during T cell activation and thus is a crucial element in regulating the anti-tumor immune response.

Researchers identify a vital protein needed to regulate anti-tumor immune response
Shao-Cong Sun, PhD. Image Credit: MD Anderson Cancer Center

The preclinical study, published recently in Nature Immunology, indicates that increasing NIK activity in T cells may be a potential approach to improve the efficacy of immunotherapy such as adoptive cellular therapies and immune checkpoint blockade.

The team used a preclinical melanoma model to assess the melanoma-specific T cells designed to exhibit higher levels of NIK. In contrast to the controls, the T cells showed stronger tumor-killing potential and enhanced survival. This indicates that increased NIK activity may enhance the effectiveness of adoptive T cell therapies.

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.”

Shao-Cong Sun, Study Corresponding Author and Professor of Immunology, MD Anderson Cancer Center

Sun explains that T cells usually occur in a relatively quiet state with little cell division and low energy requirements. But once they identify an antigen, the T cells start expanding and stimulate the glycolysis metabolic pathway to fulfill the increased energy needs for performing the immune function.

Immune checkpoint proteins such as CTLA-4 and PD-1 tightly regulate the metabolic shift and act to inhibit T cell metabolism. Therefore, immune checkpoint inhibitors can revitalize T cell anti-tumor activity by promoting metabolism.

Additionally, T cells start producing proteins known as costimulatory molecules once they are activated. These molecules act to stimulate metabolism and the immune response. The team sought to gain better insights into its role in regulating T cell function as they knew that the NIK protein functions downstream of several of these costimulatory molecules.

In models of melanoma, loss in NIK led to an increased tumor burden and reduced tumor-infiltrating T cells. This indicates that NIK plays a vital role in anti-tumor immunity and the survival of T cells.

Further studies show that NIK is important for the metabolic reprogramming in activated T cells through its control of the cellular redox system. Increased metabolism can result in higher levels of reactive oxygen species (ROS), which can impair the cell and trigger protein degradation.

The team found that NIK preserves the NADPH redox system—a vital antioxidant mechanism that reduces the accumulation of ROS. This in turn results in the stabilization of the HK2 protein—a rate-limiting enzyme included in 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. Interestingly, we found that adding more NIK to the cells, you can further increase the levels of HK2 and make glycolysis more active.”

Shao-Cong Sun, Study Corresponding Author and Professor of Immunology, MD Anderson Cancer Center

As a prospective therapeutic application, the team is now focusing on assessing the modified chimeric antigen receptor (CAR) T cells in the lab designed to overexpress NIK. Eventually, they look forward to exploring other therapeutic methods, like targeted therapies that could manipulate NIK activity together with other immunotherapy approaches, such as immune checkpoint inhibitors.

Source:
Journal reference:

Gu, M., et al. (2021) NF-κB-inducing kinase maintains T cell metabolic fitness in antitumor immunity. Nature Immunology. doi.org/10.1038/s41590-020-00829-6.

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