Breaking News
February 18, 2019 - Breast cancer screening age should be lowered to 35
February 18, 2019 - Brain synchronization depends on the language of communication
February 18, 2019 - Drug Company Payments Over Time May Influence Rx Practices
February 18, 2019 - Despite socioeconomic gains, black-white ‘health gap’ remains
February 18, 2019 - Researchers report progress in the treatment of aggressive brain tumors
February 18, 2019 - Scientists discover trigger that turns strep infections into devastating disease
February 18, 2019 - Scanning children’s teeth may predict future mental health issues
February 18, 2019 - Health Highlights: Feb. 14, 2019
February 18, 2019 - New knowledge could help predict and prevent depression
February 18, 2019 - More primary care physicians leads to longer life spans | News Center
February 18, 2019 - Patented IU discovery to treat ARDS has been optioned to Theratome Bio
February 18, 2019 - Male Y chromosomes not ‘genetic wastelands’
February 18, 2019 - Hormone therapy during gender transition may increase risk for cardiovascular events
February 18, 2019 - NICE renews accreditation for Advanced
February 18, 2019 - FDA Grants Orphan Drug Designation to Amplyx Pharmaceuticals for APX001 for Treatment of Cryptococcosis
February 18, 2019 - Molecule effective in killing tuberculosis bacteria
February 18, 2019 - Columbia researchers unravel why some glioblastomas respond to immunotherapy
February 18, 2019 - Men who are able to do ten push-ups are less likely to have a stroke
February 18, 2019 - Blood-brain barrier disruption could lead to age-related cognitive decline
February 18, 2019 - Combination of PARP inhibitor and immunotherapy results in tumor regression in SCLC mouse models
February 18, 2019 - Heavy smoking could lead to vision loss, study finds
February 18, 2019 - New diagnostic test for malaria uses spit, not blood
February 18, 2019 - New therapeutic molecules show promise in reversing memory loss related to depression, aging
February 18, 2019 - Darla Shine joins anti-vaccination campaigners
February 18, 2019 - New study outlines sex-specific issues in ischemic heart disease
February 18, 2019 - Drug combinations could become first-line treatment for metastatic kidney cancer
February 18, 2019 - Lifetime adversity, increased neural processing during trauma combine to intensify core PTSD symptoms
February 18, 2019 - HRQoL Scores Decrease With Treatment Line in Multiple Myeloma
February 18, 2019 - Convincing evidence that type 2 diabetes is a cause of erectile dysfunction
February 18, 2019 - Study offers implications of advanced age in evaluation, management of ischemic heart disease
February 18, 2019 - Children from homes with flame-retardant sofa have high SVOC concentration in their blood
February 18, 2019 - Art Institute of Chicago announces results of research on five terracotta sculptures
February 18, 2019 - New PET/CT tracer shows high detection rate for diagnosis of acute venous thromboembolism
February 18, 2019 - Smoking may blight immune response against melanoma and reduce survival
February 18, 2019 - How Inactivity and Junk Food Can Harm Your Brain
February 18, 2019 - Diabetes tops common conditions for frequent geriatric emergency patients
February 18, 2019 - Longer-lived sperm produces offspring with healthier lifespans
February 18, 2019 - New dental adhesive prevents tooth decay around orthodontic brackets
February 18, 2019 - New eHealth tool shows potential to improve quality of asthma care
February 18, 2019 - New Australian initiative helps emergency clinicians to improve patient care
February 17, 2019 - Apellis Pharmaceuticals’ APL-2 Receives Fast Track Designation from the FDA for the Treatment of Patients with Paroxysmal Nocturnal Hemoglobinuria
February 17, 2019 - Researchers identify faulty ‘brake’ that interferes with heart muscle’s ability to contract and relax
February 17, 2019 - Support from trusted adults can reduce risk of dying in suicidal teens, finds study
February 17, 2019 - Heart attack awareness improved since 2008
February 17, 2019 - Exercise gives a better brain boost to older men than women
February 17, 2019 - New research disproves previous assumptions of how looks influence personality
February 17, 2019 - Cannabis use as a teenager linked to depression later in life
February 17, 2019 - Sinks by Toilets in ICU Patient Rooms Harbor Harmful Bacteria
February 17, 2019 - Cancer cells’ plasticity makes them harder to stop
February 17, 2019 - Young cannabis users have increased risk of depression and suicidal behavior
February 17, 2019 - Tasmanian Devils Likely to Survive Cancer Scourge
February 17, 2019 - Neoadjuvant PD-1 blockade seems effective in glioblastoma
February 17, 2019 - Personal, social factors play role in enabling sustainable return to work after ill health
February 17, 2019 - Mouse studies show ‘inhibition’ theory of autism wrong
February 17, 2019 - Study shows how neuroactive steroids inhibit activity of pro-inflammatory proteins
February 17, 2019 - Use of liver grafts from older donors decreased despite better outcomes in recipients
February 17, 2019 - MUSC researchers discover new mechanism for a class of anti-cancer drugs
February 17, 2019 - HPV misconceptions are causing women to miss smear tests
February 17, 2019 - Sanofi and Regeneron Offer Praluent (alirocumab) at a New Reduced U.S. List Price
February 17, 2019 - Researchers say auditory testing can identify children for autism screening
February 17, 2019 - New method analyzes how single biological cells react to stressful situations
February 17, 2019 - WVU gynecologic oncologist investigates novel treatment for cervical and vaginal cancers
February 17, 2019 - ADHD diagnoses poorly documented
February 17, 2019 - Majority of gender minority youth do not identify with traditional sexual identity labels
February 17, 2019 - AbbVie, Teneobio enter into strategic transaction to develop potential treatment for multiple myeloma
February 17, 2019 - Lower Birth Weight May Up Risk for Psychiatric Disorders
February 17, 2019 - Scientists identify reversible molecular defect underlying rheumatoid arthritis
February 17, 2019 - Moffitt researchers shed light on how CAR T cells function mechanistically
February 16, 2019 - Female Anatomy May Play Big Role in Sperm’s Success
February 16, 2019 - BMI may mediate inverse link between fiber intake, knee OA
February 16, 2019 - Movement impairments in autism can be reversed through behavioral training
February 16, 2019 - Studies address racial disparities in postpartum period and cardiovascular health
February 16, 2019 - Scientists implicate hidden genes in the severity of autism symptoms
February 16, 2019 - Decreased deep sleep linked to early signs of Alzheimer’s disease
February 16, 2019 - Neuroscientists show how the brain responds to texture
February 16, 2019 - Gilead Announces Topline Data From Phase 3 STELLAR-4 Study of Selonsertib in Compensated Cirrhosis (F4) Due to Nonalcoholic Steatohepatitis (NASH)
February 16, 2019 - What Can I Do About Sweating? (for Teens)
February 16, 2019 - Companies navigate dementia conversations with older workers
February 16, 2019 - Newly developed stem cell technologies show promise for treating PD patients
February 16, 2019 - Collaborative material research could advance self-assembling nanomaterials
‘Hidden’ driver discovered that helps prime the anti-tumor immune response

‘Hidden’ driver discovered that helps prime the anti-tumor immune response

image_pdfDownload PDFimage_print
In this study, authors used an interdisciplinary approach, integrating systems biology with the immunology expertise. (Study authors Xingrong Du, Hongbo Chi and Jiyang Yu). Credit: St. Jude Children’s Research Hospital

Like exposing a crime boss whose authority has gone undetected, St. Jude Children’s Research Hospital scientists have identified a hidden driver that influences production of the T cells that fight cancer and infections. The study appears today as an advance online publication in the journal Nature.

The hidden drivers are kinases (enzymes) Mst1 and Mst2. Researchers showed Mst1 and Mst2 work together to regulate the function of different dendritic cell types (subsets). Dendritic cells are key regulators of the adaptive immune system, including the T cells that are central to cancer immunotherapy.

“Dendritic cells are crucial for activating the adaptive immune response, including priming anti-tumor T cells,” said Hongbo Chi, Ph.D., a member of the St. Jude Department of Immunology. “But regulation of the distinct functions of different dendritic cell subsets have been poorly understood. We wanted to change that.

“These findings provide clues for new treatment strategies for cancer or immune disorders by modulating the activity of dendritic cells to shape the immune response,” said Chi, who is co-corresponding author of the research with Jiyang Yu, Ph.D., an assistant member of the St. Jude Department of Computational Biology. Xingrong Du, Ph.D., a postdoctoral fellow in Chi’s laboratory, is the first author.

Taking a Systems Approach

A data-driven, systems biology algorithm called NetBID played a key role in the research. Yu and his colleagues developed NetBID, short for data-driven network-based Bayesian inference of drivers.

Yu and his team integrated gene expression, whole proteomics and phosphorylated proteomics data from Chi’s laboratory and other sources to reverse engineer biologic networks in mouse dendritic cells. Researchers used NetBID to analyze differences in networks of the different dendritic cell subtypes. To their surprise, Mst1/2 and the Hippo signaling pathway emerged as a key regulator of dendritic cell function and the T cell response.

“The Hippo pathway is known for regulating organ size in animals, not immune function in dendritic cells,” Chi said. Yu compared Mst1/2 to a crime boss whose role is concealed behind several layers of subordinates. “A data-driven systems approach gave us a way to find the hidden drivers that underlie the differential functions of the dendritic cell subsets,” Yu said.

A data-driven, systems biology algorithm called NetBID played a key role in the research. Yu and his colleagues developed NetBID, to analyze differences in networks of the different dendritic cell subtypes. An example of the NetBID network used for this study. Credit: Jiyang Yu / St. Jude Children’s Research Hospital

Interdisciplinary collaboration was essential to the research, Chi added.

Metabolism and Signaling

This study focused on dendritic cell subsets that have distinct effects on the immune system. One, CD8α+ dendritic cells, primes production of CD8 T cells central to fighting tumors and infections. The other, CD8α- dendritic cells, primes production of a different T cell subtype.

Researchers compared metabolic activity in the different dendritic cells and found that the CD8α+ dendritic cells were more metabolically active than CD8α- dendritic cells. They reached that conclusion by comparing oxygen metabolism in the cells’ power plants, mitochondria. Investigators also showed that manipulating metabolism affected CD8α+ dendritic cell function and T cell priming.

“While metabolism is known to be important generally in the immune response, this study defines, we believe for the first time, that not only is it important in dendritic cell function, but that the two dendritic cell subsets have distinct metabolism controlled by Hippo signaling,” Chi said. “In addition, we showed that manipulating metabolism directly affects function of the dendritic cell subset.”

Researchers also showed that Mst1/2 played a pivotal role in cytokine signaling, which is essential for priming T cells and ensuring a robust immune response. Cytokines are small secreted molecules that modulate the immune response.

Rather than working through the conventional signaling pathways, investigators showed that Mst1/2 takes an unconventional route to prime T cells. Mst1/2 uses the NF-κB signaling pathway rather than convention pathways to trigger production of the cytokine interleukin-12 (IL-12). IL-12 promotes CD8α+ dendritic cell function and primes CD8 T cell responses.

“The research shows that Mst1/2 integrate metabolic activity and cytokine signaling to selectively drive CD8α+ dendritic cell function,” Chi said.

“The NetBID algorithm can be used to mine other datasets for hidden drivers and explore biological questions,” Yu said. “The algorithm has already been used to analyze network differences among different cancer subtypes or between drug-resistant and sensitive cancer patients for identification of potential therapeutic targets and biomarkers. The key is data-driven and context-specific networks,” he said.


Explore further:
Study provides insights on immune cells involved in kidney disease

More information:
Hippo/Mst signaling couples metabolic state and immune function of CD8a+dendritic cells, Nature (2018). DOI: 10.1038/s41586-018-0177-0 , www.nature.com/articles/s41586-018-0177-0

Journal reference:
Nature

Provided by:
St. Jude Children’s Research Hospital

Tagged with:

About author

Related Articles