Breaking News
November 18, 2018 - Using light to control crucial step in embryonic development
November 18, 2018 - Unusual case of father-to-son HIV transmission reported
November 18, 2018 - FDA Approves Aemcolo (rifamycin) to Treat Travelers’ Diarrhea
November 18, 2018 - Poverty blamed on widening north-south gap in young adult deaths in England
November 18, 2018 - Progress in meningitis lags far behind other vaccine-preventable diseases, analysis shows
November 18, 2018 - Consensus Statement Issued on Management of Foot, Ankle Gout
November 18, 2018 - Fine particle air pollution is a public health emergency hiding in plain sight
November 18, 2018 - In-hospital mortality higher among patients with drug-resistant infections
November 17, 2018 - Research shines new, explanatory light on link between obesity and cancer
November 17, 2018 - FIND explores new diagnostic assays for confirmatory HCV diagnosis in community settings
November 17, 2018 - Tracking Preemies’ Head Size May Yield IQ Clues
November 17, 2018 - Scientists call for unified standards in 3-D genome and epigenetic data
November 17, 2018 - Lab Innovations 2018 has beaten all records by attracting 3,113 attendees
November 17, 2018 - Sexuality education before age 18 may reduce risk of sexual assault in college
November 17, 2018 - New model of FSHD could be useful to study effectiveness of experimental therapeutics
November 17, 2018 - FDA approves antibacterial drug to treat travelers’ diarrhea
November 17, 2018 - Lab Innovations 2018 confirmed as a major hit with visitors, exhibitors and speakers
November 17, 2018 - Largest parasitic worm genetic study hatches novel treatment possibilities
November 17, 2018 - UCLA biologists uncover how head injuries can lead to serious brain disorders
November 17, 2018 - Static and dynamic physical activities offer varying protection against heart disease
November 17, 2018 - Obesity significantly increases risk of Type 2 diabetes and coronary artery disease
November 17, 2018 - People with rare cancers can benefit from genomic profiling, shows research
November 17, 2018 - NIH awards over $1.8 million to husband-and-wife doctors to test new breast cancer approach
November 17, 2018 - Four-in-one antibody used to fight flu shows promise in mice
November 17, 2018 - New approach allows pathogens to be starved by blocking important enzymes
November 17, 2018 - Higher body mass index could cause depression even without health problems
November 17, 2018 - Protein which plays role in sensing cell damage serves as new target to treat pulmonary hypertension
November 17, 2018 - FDA Approves Adcetris (brentuximab vedotin) in Combination with Chemotherapy for Adults with Previously Untreated Systemic Anaplastic Large Cell Lymphoma or Other CD30-Expressing Peripheral T-Cell Lymphomas
November 17, 2018 - ID specialist input improves outcomes for outpatient parenteral antimicrobial therapy
November 17, 2018 - UT Southwestern scientists selected to receive 2019 Edith and Peter O’Donnell Awards
November 17, 2018 - New clinical algorithm to help individuals manage type 2 diabetes when fasting during Ramadan
November 17, 2018 - Researchers identify LZTR1 as evolutionarily conserved component of RAS pathway
November 17, 2018 - Heart Disease Leading Cause of Death in Low-Income Counties
November 17, 2018 - Estrogen Levels Test: MedlinePlus Lab Test Information
November 17, 2018 - Research reveals link between immunity, diabetes
November 17, 2018 - Research shows how to achieve improved smoking cessation outcomes within California’s Medicaid population
November 17, 2018 - New study finds less understanding and implementation of patient engagement
November 17, 2018 - New shoe insole technology could help diabetic ulcers heal better while walking
November 17, 2018 - New method to extend cell division and immortalization of avian-derived cells
November 17, 2018 - Australian Academy of Science urges parents to vaccinate children against meningococcal disease
November 17, 2018 - Hot water treatment may help improve inflammation and metabolism in sedentary people
November 17, 2018 - Researchers produce 3D chemical maps of small biological samples
November 17, 2018 - Must Blood Pressure Rise Wth Age? Remote Tribes Hold Clues
November 17, 2018 - Noonan Syndrome
November 17, 2018 - Interventions to delay and prevent type 2 diabetes are underused, researchers say
November 17, 2018 - Hackathon prize winner seeks to remotely monitor patient skin conditions
November 17, 2018 - Research team identifies Ashkenazi Jewish founder mutation for Leigh syndrome
November 17, 2018 - Gene editing could be used to halt kidney disease in patients with Joubert syndrome
November 17, 2018 - Study uncovers link between gut disruption and aging
November 17, 2018 - Teens more likely to pick up smoking after exposure from friends and family
November 17, 2018 - Nicoya designate the Institute for Stem Cell Biology and Regenerative Medicine as the OpenSPR Centre of Excellence
November 17, 2018 - new horizon in dental, oral and craniofacial research
November 17, 2018 - How does poor air quality affect your health?
November 17, 2018 - New device can regulate children’s blood glucose more like natural pancreas
November 17, 2018 - Game-Changers in Western Blotting and Protein Analysis
November 17, 2018 - FDA announces new actions to limit sale of e-cigarettes to youth
November 17, 2018 - Warmer winter temperatures related to higher crime rates
November 17, 2018 - MCO places increasing emphasis on helping people find and access healthy food
November 17, 2018 - Group of students aim to improve malaria diagnosis using old smartphones
November 17, 2018 - Transplantation of feces may protect preterm children from deadly bowel disease
November 17, 2018 - Researchers explore whether low-gluten diets can be recommended for people without allergies
November 17, 2018 - New and better marker for assessing patients after cardiac arrest
November 17, 2018 - For 7-year-old with failing bone marrow, a life-saving transplant | News Center
November 17, 2018 - New first-line treatment for peripheral T-cell lymphoma approved by FDA
November 17, 2018 - Artificial intelligence could be valuable tool to help young victims disclose traumatic testimony
November 17, 2018 - Breakthrough in the treatment of Restless Legs Syndrome
November 16, 2018 - FDA Approves Keytruda (pembrolizumab) for the Treatment of Patients with Hepatocellular Carcinoma (HCC) Who Have Been Previously Treated with Sorafenib
November 16, 2018 - Eagle Books | Native Diabetes Wellness Program
November 16, 2018 - Patients with common heart failure more likely to have lethal heart rhythms
November 16, 2018 - How AI could help veterinarians code their notes | News Center
November 16, 2018 - Bias-based bullying does more harm to students than generalized bullying
November 16, 2018 - Researchers find first direct evidence that cerebellum plays role in cognitive functions
November 16, 2018 - Non-coding genetic variant plays key role in endothelial function and disease incidence
November 16, 2018 - EMA recommends first all-oral treatment to tackle deadly sleeping sickness
November 16, 2018 - Drug used to treat dizziness may slow down growth of triple-negative breast cancer
November 16, 2018 - AHA: Icosapent Ethyl Cuts CV Risk From Elevated Triglycerides
November 16, 2018 - ‘Orphan’ RNAs make cancer deadlier, but potentially easier to diagnose
November 16, 2018 - Air Cube touches down at hospital | News Center
November 16, 2018 - CRISPR-based tool shown to enhance cell-based immunotherapy
November 16, 2018 - Mechanisms that govern HIV latency differ in the gut and blood, finds study
Typical mutation in brain cancer cells stifles immune response

Typical mutation in brain cancer cells stifles immune response

image_pdfDownload PDFimage_print
Mutated IDH1: Replacing a single amino acid blocks the body’s defenses and thwarts immune therapies of brain tumors. Credit: German Cancer Research Center

The exchange of a single amino acid building block in a metabolic enzyme can lead to cancer. In addition, it can impair the immune system, according to scientists from the German Cancer Research Center (DKFZ), the University Hospitals in Mannheim and Heidelberg, and the German Cancer Consortium. It thus blocks the body’s immune response in the battle against the mutant molecule and also impedes immunotherapy against brain cancer. This finding opens new insights into cancer development and progression and it also suggests that rethinking antitumor immunotherapy is required.

Alterations in the genetic material are often the first step in carcinogenesis. In many cases, an exchange of a single amino acid building block is all it takes. A prime example for this is the mutant form of a metabolic enzyme called IDH1 (isocitrate dehydrogenase 1). This enzyme has an important task in cellular energy metabolism. However, if IDH1 has undergone an alteration at a specific site, it leads to the formation of a substance called 2 HG, which harms the body. It disturbs the metabolism and stimulates cell division, thus laying the cornerstone for cancer. The scientific term for a cancerogenic metabolic product like 2-HG is “oncometabolite.” 2-HG accounts for more than 70 percent of all low-grade gliomas, a type of brain cancer.

Scientists from the German Cancer Research Center and the University Hospitals in Mannheim and Heidelberg have now found that the oncometabolite additionally impairs the body’s immune response. Normally, the immune system recognizes mutant IDH1 as foreign. The altered molecule in the tumor should therefore attract immune cells. Based on this finding, scientists already developed a vaccine that sensitizes the immune system for the battle against brain tumors exhibiting the special IDH1 mutation.

However, the opposite is the case, according to Michael Platten, a neurologist who leads a research department at the DKFZ and is director of the Neurology Department of University Medicine Mannheim (UMM). “In the immediate environment of tumors with the specific mutation in IDH1, we find only very small quantities of immune cells, which are additionally impaired in their functioning,” Platten said. “This made us curious and we aimed to find out whether and how the 2-HG oncometabolite directly influences the immune system.”

The investigators discovered that the tumor cells release 2-HG into their environment. T cells—immune cells of the body with an important role in the fight against cancer cells—take up released 2-HG. This subsequently blocks important signaling pathways in the T cells and the immune cells are re-programmed from an active to an inactive state.

“This might explain why the immune system fails to suppress the development of these tumors even though it is essentially capable of fighting tumor cells with the mutant IDH1 molecule,” said Lukas Bunse, DKFZ and Heidelberg University Hospital, who is one of the first authors of the publication in Nature Medicine. However, the scientists have also found a method to avoid this blockade. They administered an inhibitor developed by the team led by DKFZ researcher Andreas Deimling to mice with IDH1 mutant tumors. The inhibitor blocks the mutant IDH1 molecule so that no 2-HG forms in the tumor cells. Subsequently, the investigators in fact found larger quantities of active immune cells in the tumors and their immediate environment. In addition, immunotherapy combined with the inhibitor was substantially more effective.

Platten thinks that this finding has potential of learning more about other tumors and their treatment. “We now know several of these oncometabolites in different tumor types,” the neuroimmunologist said. “It would be interesting to investigate whether suppression of the immune response might be a higher principle in oncometabolites.”

The results obtained by the DKFZ researchers already point in a new direction in the treatment of IDH1 mutant tumors. “In future immunotherapies, we will have to attack from two sides,” according to Platten, because it has become clear that it is not enough to prime the body’s defense mechanisms to attack the mutant IDH1 molecule. “We must additionally block the target protein using a specific inhibitor in order to prevent the production of 2-HG and the resulting suppression of immune response.”


Explore further:
First positive results toward a therapeutic vaccine against brain cancer

More information:
Lukas Bunse et al, Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate, Nature Medicine (2018). DOI: 10.1038/s41591-018-0095-6

Journal reference:
Nature Medicine

Provided by:
German Cancer Research Center

Tagged with:

About author

Related Articles