(Press-News.org) HOUSTON -- Researchers at The University of Texas MD Anderson Cancer Center 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.
The preclinical research, published today in Nature Immunology, suggests that elevating NIK activity in T cells may be a promising strategy to enhance the effectiveness of immunotherapy, including adoptive cellular therapies and immune checkpoint blockade.
In a preclinical melanoma model, the researchers evaluated melanoma-specific T cells engineered to express higher levels of NIK. Compared to controls, these T cells displayed stronger tumor-killing abilities and improved survival, suggesting that increasing NIK activity may improve 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," said corresponding author Shao-Cong Sun, Ph.D., professor of Immunology. "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."
T cells generally exist in a relatively quiet state with low energy demands and little cell division, Sun explained. However, upon recognizing an antigen, T cells begin expanding and activate the glycolysis metabolic pathway to meet the increased energy demands of carrying out their immune function.
This metabolic shift is closely regulated by immune checkpoint proteins, such as CTLA-4 and PD-1, which act to repress T cell metabolism. Thus, immune checkpoint inhibitors can reinvigorate T cell anti-tumor activity by boosting metabolism. In addition, T cells begin producing proteins called costimulatory molecules after they become activated, which work to stimulate metabolism and the immune response.
Knowing 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, an important antioxidant mechanism to reduce the accumulation of ROS. This 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."
As a potential therapeutic application, the researchers currently are working to evaluate modified chimeric antigen receptor (CAR) T cells in the laboratory engineered to overexpress NIK. In the future, they hope to explore other therapeutic approaches, such as targeted therapies that could manipulate NIK activity in tandem with other immunotherapy approaches, including immune checkpoint inhibitors.
INFORMATION:
The research was supported by the National Institutes of Health (GM84459, 30CA016672 and IS10OD01230), the National Research Foundation of Korea (MISP 2011-0018312) and the Cancer Prevention & Research Institute of Texas (RP130397).
In addition to Sun, collaborating MD Anderson authors include Meidi Gu, Ph.D., Xiaofei Zhou, Ph.D., Le-Le Zhu, Ph.D., Zuliang Jie, Ph.D., Xiaoping Xie, Ph.D., Yaoyao Shi, Ph.D., and Xuhong Cheng all of Immunology; Jin-Young Yang, Ph.D., of Immunology and Busan National University, Busan, South Korea; Xiaofeng Zheng, and Jing Wang, Ph.D., of Bioinformatics & Computational Biology. Additional co-authors include Jee Hyung Sohn and Jae Bum Kim, Ph.D., both of Seoul National University, Seoul, Korea; Jie Yang, Ph.D., of Precision for Medicine, Houston, TX; and Hans D. Brightbill, Ph.D., of Genentech, South San Francisco, CA. A full list of disclosures can be found with the paper here.
- 30 -
HOUSTON -- Researchers from The University of Texas MD Anderson Cancer Center who profiled more than 45,000 individual cells from patients with peritoneal carcinomatosis (PC), a specific form of metastatic gastric cancer, defined the extensive cellular heterogeneity and identified two distinct subtypes correlated with patient survival.
Based on their findings, published today in Nature Medicine, the researchers developed and validated a gene expression signature capable of predicting patient survival better than other clinical features. If validated in prospective studies, this tool may be useful in stratifying ...
EUGENE, Ore. -- Jan. 4, 2021 -- Phosphorous, calcium and charcoal in spotty patches of fertile soil in the Amazon rainforest suggest that natural processes such as fires and river flooding, not the ingenuity of indigenous populations, created rare sites suitable for agriculture, according to new research.
The presence of pre-Columbian artifacts and signs of plant domestication uncovered in the region's fertile soil, commonly called Amazonian dark earth, had been thought to mean that agricultural practices, including controlled burning, by indigenous people had boosted soil nutrients.
However, radiocarbon dating ...
What The Study Did: Denmark was one of the first countries to enforce lockdown to reduce the spread of COVID-19 and subsequent gradual reopening, whereas Sweden has had few restrictions, largely limited to public recommendations. Researchers assessed public mobility and social media attention associated with COVID-19 spread and societal interventions from February to June in Denmark and Sweden.
Authors: Isabell Brikell, Ph.D., of the Karolinska Institutet in Stockholm, is the corresponding author.
To access the embargoed study: Visit our For The Media website at ...
What The Study Did: Researchers used health insurance data from Taiwan to investigate the risk of substance use disorder among patients with autism spectrum disorder and its associations with risk of death.
Authors: Chih-Sung Liang, M.D., of the National Defense Medical Center, and Mu-Hong Chen, M.D., Ph.D., of the Taipei Veterans General Hospital in Taipei, Taiwan, are the corresponding authors.
To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/
(doi:10.1001/jamapediatrics.2020.5371)
Editor's Note: The article includes funding/support disclosures. Please see the article for additional information, including other authors, author ...
Bitterling fishes (Subfamily: Acheilognathinae) spawn in the gills of living freshwater mussels obligately depending on the mussels for reproduction. On the Matsuyama Plain, Japan, populations of unionid mussels--Pronodularia japanensis, Nodularia douglasiae, and Sinanodonta lauta--have decreased rapidly over the past 30 years. Simultaneously, the population of a native bitterling fish, Tanakia lanceolata, which depends on the three unionids as a breeding substrate, has decreased. Furthermore, a congeneric bitterling, Tanakia limbata, has been artificially introduced, and hybridisation and genetic introgression occur between them. Here, we surveyed the reproduction and occurrence of hybridisation between native and invasive species ...
Improving solar cell design is integral for improving energy consumption. Scientists have lately focused on making solar cells more efficient, flexible, and portable to enable their integration into everyday applications. Consequently, novel lightweight and flexible thin film solar cells have been developed. It is, however, not easy to combine efficiency with flexibility. For a material (usually a semiconductor) to be efficient, it must have a small "band gap"--the energy required to excite charge carriers for electrical conduction--and should absorb and convert a large portion of the sunlight into electricity. Till date, no such efficient absorber suitable for thin film solar cells has been developed.
Typically, charge carriers in a semiconductor are ...
Osaka, Japan - A cancer-specific L-type amino acid transporter 1 (LAT1) is highly expressed in cancer tissues. Inhibiting the function of LAT1 has been known to have anti-tumor effects, but there has been limited progress in the development of radionuclide therapy agents targeting LAT1. Now, a multidisciplinary research team at Osaka University has established a targeted alpha-therapy with a novel drug targeting LAT1.
The researchers first produced the alpha-ray emitter 211Astatine, no easy task given that Astatine (At) is the rarest naturally occurring element on Earth. Targeted alpha-therapy selectively delivers α-emitters to tumors; the advantage over conventional β-therapy is that alpha ...
The odd, wavy pattern that results from viewing certain phone or computer screens through polarized glasses has led researchers to take a step toward thinner, lighter-weight lenses. Called moiré, the pattern is made by laying one material with opaque and translucent parts at an angle over another material of similar contrast.
A team of researchers from Tokyo University of Agriculture and Technology, TUAT, in Japan have demonstrated that moiré metalenses--tiny, patterned lenses composed of artificial "meta" atoms--can tune focal length along a wider range than previously seen. They published their results on November ...
Mothers and fathers of children diagnosed with cancer are affected financially in different ways. While mothers' incomes fall in the short term and then rise, the adverse financial repercussions on fathers occur later. Researchers at Uppsala University have investigated the socioeconomic impact on parents of having a child diagnosed with cancer. The study is published in the International Journal of Cancer.
Previous research has shown that when a child falls ill with cancer, the parents are affected financially as well as psychologically. The available literature shows that mothers are more affected than ...
High-performance, eco-friendly, safe and at the same time cost-effective: the zinc-air battery is an attractive energy storage technology of the future. Until now, the conventional zinc-air battery has struggled with a high chemical instability, parasitic reactions which rooted in the usage of alkaline electrolytes lead to electrochemical irreversibility. Based on an innovative, non-alkaline, aqueous electrolyte, an international research team led by scientist Dr. Wei Sun of MEET Battery Research Center at the University of Muenster has developed a new battery chemistry for the zinc-air battery which overcomes the previous technical obstacles. The scientific team has published the detailed results of their research project, involving ...
