Nat Immunol: Key proteins are involved in T-cell metabolism and anti-tumor immune response

January 5, 2021 // -- Researchers at the University of Texas MD Anderson Cancer Center have found that a protein called NF-B-induced kinase (NIK) is critical to changes in metabolic activity caused by T-cell activation, making it a key factor in regulating T-cell anti-tumor activity.
preclinical study published today in the journal Nature Immunology suggests that increasing NIK activity in T-cells may be a promising strategy to enhance the effectiveness of immunotherapy, including T-cell transplantation and immune checkpoint blocking.
in preclinical melanoma models, the researchers evaluated melanoma-specific T cells modified to express higher levels of NIK.
T-cells showed greater tumor damage and improved survival compared to the control group, suggesting that increased NIK activity could improve the effectiveness of T-cell therapy.
(Photo Source: www.pixabay.com) "NIK is a new type of T-cell metabolic regulator with a unique effect.
Biologically, NIK activity stabilizes HK2 glycolyzyme enzymes by regulating the redox pathways of cells," said co-author Dr. Shao-Cong Sun.
," Sun explains, T-cells usually exist in a relatively quiet state, with lower energy requirements and very little cell division.
, however, after identifying antigens, T-cells begin to amplification and activate the glycolysis metabolic pathway to meet the increased energy needs of performing their immune functions.
this metabolic change is strictly regulated by immunosupergenic proteins such as CTLA-4 and PD-1, which inhibit the metabolism of T cells.
, immunosuppressants can enhance the anti-tumor activity of T cells by promoting metabolism.
, T cells are activated to produce proteins called costulation molecules that stimulate metabolism and immune response.
know that NIK proteins work downstream of many of these costulating molecules and are looking for a better understanding of their role in regulating T-cell function.
in melanoma models, NIK loss leads to an increased tumor burden and a decrease in tumor-immersive T-cells, indicating that NIK plays a vital role in anti-tumor immunity and T-cell survival.
further experiments have shown that NIK is essential for reprogramming metabolism in active T cells by controlling the cell redox system.
metabolism can lead to elevated levels of reactive oxygen (ROS), which damages cells and stimulates protein degradation.
researchers found that NIK maintains a NADPH redox system, an important antioxidant mechanism to reduce THES accumulation.
this leads to the stabilization of the HK2 protein, which is a speed limit enzyme in the glycolysis pathway.
S. Sun said: "Our findings suggest that without NIK, the HK2 protein would be unstable and degrade continuously.
you need NIK to maintain the level of HK2 in T cells.
, we found that adding more NIKs to cells can further increase HD2 levels and make glycolysis more active.
, they hope to explore other treatments, such as targeted treatments that manipulate NIK activity with other immunotherapy treatments, including immuno-checkpoint inhibitors.
() Source: Immunology finds protein critical to T cell metabolism and anti-tumor immune response Original source: Gu, M., Zhou, X., Sohn, J.H. et al. NF-κB-inducing kinase maintains T cell metabolic fitness in antitumor immunity. Nat Immunol (2021). doi.org/10.1038/s41590-020-00829-6