Breaking News
March 23, 2019 - Trigger warnings have minimal impact on how people respond to content, shows research
March 23, 2019 - Gilead Announces Data From Two Studies Supporting Further Development of GS-6207, a Novel, Investigational HIV-1 Capsid Inhibitor as a Component of Future Long-Acting HIV Therapies
March 23, 2019 - Selfish genetic elements amplify inflammation and age-related diseases
March 23, 2019 - Study provides new understanding of how the brain recovers from damage caused by stroke
March 23, 2019 - CRISPR/Cas libraries could revolutionize drug discovery
March 23, 2019 - Allergic reaction during pregnancy may alter sexual-development in offspring’s brain
March 23, 2019 - Seeing through a robot’s eyes helps those with profound motor impairments
March 23, 2019 - Recent research shows that ease of breastfeeding after C-section differs culturally
March 23, 2019 - Newly discovered parameters offer more control over efficient release of drugs
March 23, 2019 - ‘De-tabooing’ of abortion- Women would like more support from health care community
March 23, 2019 - Anti-TB drugs can increase susceptibility to Mtb reinfection
March 23, 2019 - New survey indicates need of attention to neglected tropical diseases
March 23, 2019 - Innovative in vitro method to develop easy-to-swallow medicine for children and older people
March 23, 2019 - Sugary drinks could raise risk of early deaths finds study
March 23, 2019 - Lian wins ENGINE grant for stem-cell-based therapy to treat Type 1 diabetes
March 23, 2019 - Overall, Physicians Are Happy and Enjoy Their Lives
March 23, 2019 - Researchers discover how blood vessels protect the brain during inflammation
March 23, 2019 - CDC study shows modest improvement in optimal hospital breastfeeding policy
March 23, 2019 - Family-based prevention program to reduce alcohol use among older teens
March 23, 2019 - Remote monitoring of implanted defibrillators in heart failure patients prevents hospitalizations
March 23, 2019 - Appropriate doffing of personal protective equipment may reduce healthcare worker contamination
March 23, 2019 - Window screens can suppress mosquito populations, reduce malaria in Tanzania
March 23, 2019 - Researchers discover new biomarker for postoperative liver dysfunction
March 23, 2019 - Pregnancy history may be linked to cognitive function in older women, finds study
March 23, 2019 - Study shows ticagrelor is equally safe and effective as clopidogrel after heart attack
March 23, 2019 - FDA Approves First Drug for Postpartum Depression, Zulresso (brexanolone)
March 23, 2019 - New guidelines outline new treatment management for psoriasis
March 23, 2019 - Thermally abused cooking oil may promote progression of breast cancer
March 23, 2019 - High-fructose corn syrup fuels growth of colon tumors in mice
March 23, 2019 - Partnership aims at establishing best practices to promote diversity in clinical trials
March 23, 2019 - New study examines presence of microbes in tap water from residences, office buildings
March 23, 2019 - Early life trauma may affect brain structure, contribute to major depressive disorder
March 23, 2019 - NIH starts clinical trial of drug to treat cravings associated with opioid use disorder
March 23, 2019 - Cervix bacteria, immune factors could be a warning signal of premature birth, reports new research
March 23, 2019 - Worst-ever emergency care performance figures underscore the need to focus on staffing
March 23, 2019 - The Current issue of “The view from here” is concerned with Cancer
March 23, 2019 - Mouse model validates how ‘good’ and ‘bad’ bacteria affect acne
March 23, 2019 - Individual amygdala neurons respond to touch, imagery and sounds
March 23, 2019 - Combination of two topical creams can prevent cancer
March 23, 2019 - Study suggests depression screening when assessing African-Americans for schizophrenia
March 23, 2019 - New electronic support system for choosing drug treatment based on patient’s genotype
March 23, 2019 - First-of-its-kind study provides pregnancy statistics of imprisoned U.S. women
March 23, 2019 - Marinus Pharmaceuticals Initiates Phase 3 Study in Children with PCDH19-Related Epilepsy
March 23, 2019 - Laparoscopy: MedlinePlus Lab Test Information
March 23, 2019 - Shellfish allergies: can they be treated?
March 23, 2019 - Toilet seat heart monitoring system
March 23, 2019 - Researchers identify way to improve common treatment for PTSD
March 23, 2019 - High potency cannabis use linked to psychosis finds study
March 23, 2019 - Evoke Pharma Submits Response to FDA Review Letter for Gimoti NDA
March 23, 2019 - Tracking HIV’s ever-evolving genome in effort to prioritize public health resources
March 23, 2019 - Scientists grow most sophisticated brain organoid to date
March 23, 2019 - ADHD drug raising risk of psychosis
March 22, 2019 - FDA approves brexanolone, first drug developed to treat postpartum depression
March 22, 2019 - Gruesome cat and dog experiments by the USDA exposed
March 22, 2019 - Ball pits used in children’s physical therapy may contribute to germ transmission
March 22, 2019 - Long-term use of inexpensive weight-loss drug may be safe and effective
March 22, 2019 - FDA Approves Sunosi (solriamfetol) for Excessive Daytime Sleepiness Associated with Narcolepsy or Obstructive Sleep Apnea
March 22, 2019 - Anti-Müllerian Hormone Test: MedlinePlus Lab Test Information
March 22, 2019 - Finding the right exercise, diet aids for HIV patients
March 22, 2019 - Health Plans For State Employees Use Medicare’s Hammer On Hospital Bills
March 22, 2019 - Researchers develop new tool for imaging large groups of neurons in living animals
March 22, 2019 - Certain bacteria and immune factors in vagina may cause or protect against preterm birth
March 22, 2019 - Research identifies guidelines for prioritizing hepatitis C treatment in U.S. prisons
March 22, 2019 - Novel breath test could pave new way to non-invasively measure gut health
March 22, 2019 - Pharmaceutical and personal care products may result in new contaminants in waterways
March 22, 2019 - New model could revolutionize the way researchers investigate spread of pathogens
March 22, 2019 - MSU professor receives NSF CAREER grant for biosensor diagnostics
March 22, 2019 - High-fat, high-sugar diet in mouse mothers causes problems in the hearts of offspring
March 22, 2019 - ACC: Catheter Ablation Does Not Cut Mortality, Stroke in A-Fib
March 22, 2019 - Wiedemann-Rautenstrauch syndrome – Genetics Home Reference
March 22, 2019 - Health insurance is not assurance of healthcare
March 22, 2019 - Supporting “curiosity-driven research” at the Discovery Innovation Awards
March 22, 2019 - Must-Reads Of The Week (Some Flying Below The Radar)
March 22, 2019 - Newly engineered nanoscale protein micelles can be tracked by MRI
March 22, 2019 - New model more effective in predicting risk of opioid overdose than traditional models
March 22, 2019 - Mayo Clinic study identifies potential new drug therapy for liver diseases
March 22, 2019 - Pitt engineers win $550,000 NSF CAREER award to develop new intervention for people with ASD
March 22, 2019 - Early discharge does not increase readmission risk for patients after lung surgery
March 22, 2019 - Creating diverse pool of trained scientists to address Alzheimer’s research needs
March 22, 2019 - Surprising discovery offers clues to limit graft-vs.-host disease
Study shows how machinery within immune system activates T cells to attack cancer

Study shows how machinery within immune system activates T cells to attack cancer

image_pdfDownload PDFimage_print

In just a few years, CAR T-cell and other adoptive T-cell therapies have emerged as among the most promising forms of cancer immunotherapy. But even as these agents prove themselves against several forms of leukemia and lymphoma – and, potentially, certain solid tumors – basic questions remain about how they work.

In a study published online today by the journal Immunity, scientists at Dana-Farber Cancer Institute, Harvard Medical School, Vanderbilt University and colleagues at other institutions show how machinery within immune system T cells responds to outside signals and activates the cells to attack cancerous, infected, or otherwise diseased cells. The findings, based on 15 years of painstaking work to recreate and assemble key components of the signal-processing mechanism, may help researchers fine-tune T-cell therapies to the requirements of individual patients, the study authors say.

T cells, whose surfaces are dotted with structures known as T-cell antigen receptors (TCRs), patrol the body for signs of infection or other disease. As they keep watch, their TCRs lock onto bits of proteins, called antigens, displayed on protein structures decorating the surface of other cells in the human body. The antigens reveal whether a cell is normal or diseased. If a cell is diseased, these “protein bit flags” are recognized as “foreign” and, the T cell switches on, or activates, to kill the diseased cell. In CAR T-cell therapy, billions of a patient’s T cells are removed and engineered to produce a structure called a chimeric antigen receptor, or CAR, that recognizes and latches on to a cancer cell. The resulting CAR T cells – essentially, high-performance versions of ordinary T cells – are then infused into the patient, where they take up the battle against tumor cells. Other TCR immunotherapies use genetically engineered T cells employing natural TCRs rather than chimeric receptors to target specific tumor cell antigens, also called neoantigens. Of note, in every healthy human being there are billions of distinct T cells each bearing unique TCRs and collectively capable of recognizing the myriad antigens that identify diseased cells.

“While CAR T cells, and T cells in general, are often effective in identifying and killing tumor cells, the precise mechanism by which the TCR works hasn’t been clear,” says the study’s lead author, Kristine Brazin, PhD, of Dana-Farber and Harvard Medical School. “How is the signal, which originates when the receptor links to a tumor antigen, transmitted through the cell membrane into the cell interior leading to cell activation?”

Answering that question involved a deep dive into the intricacies of the TCR. Far from being a rigid, seamless object, the receptor consists of eight distinct subunits which can move as the TCR operates, even dissociating one subunit pair from one another in a highly choreographed manner.

The most prominent features of the TCR are two long components, dubbed α and β, which are unique to each individual T cell and extend like pincers from the cell membrane to snare a particular cell antigen. Beside α and β, there are six other CD3 subunits common to all TCRs involved in signaling the T cell that the specific pincer has detected antigen. Scientists have had a clear picture of the portions of the TCR that rise from the surface of the cell but knew little about the portions that anchor the receptor in the T-cell membrane.

Brazin and her colleagues focused on the α region of the TCR. Using nuclear magnetic resonance technology, they determined the structure of the section of TCRα implanted in the membrane. Here a surprise was in store.

“The assumption had been that this region, known as the transmembrane segment, was always straight,” Brazin relates. “We found, however, that it is sometimes bent in an L-shaped formation.”

When configured like an L, the segment remains largely within the cell membrane. When, like a flexible straw, it straightens up, one end pokes into the cell interior.

“We wanted to understand why this segment is sometimes embedded so shallowly in the membrane – in an L shape,” Brazin relates. “We tried to make it straight.”

To do that, she and her colleagues made mutant versions of two protein residues that cling to the sides of the transmembrane segment. Mutating one of those residues, called Arg251, caused the segment to become slightly more embedded in the membrane. Mutating the other, Lys256, made it become much more deeply immersed. Other residues were found to regulate the interconversion between bent and straight forms, with the latter jutting further through the cell membrane.

It was on the surface of the cell, however, that this bending and unbending made the biggest difference. When the transmembrane segment is in full L-shape, it presses tightly against the CD3 subunits at its side. When it unbends a little – as when Arg 251 was mutated – that tightness relaxes a bit, and the T cell enters an early stage of activation. When it becomes more fully immersed in the cell membrane, the gap with CD3 widens further and the T cell enters a later stage of activation, ready to attack tumor cells.

“The looser the connection between the transmembrane segment and CD3 subunits, the higher the state of T cell activation,” Brazin remarks. “Our findings suggest that the mechanical force of the TCR’s interaction with antigens during T cell movement initiates T cell activation by weakening the connection between the transmembrane segment and CD3.”

The finding suggests that small-molecule drugs or genetic engineering approaches that widen or narrow the space between the transmembrane segment and CD3 could be used to tune the strength of T-cell attack on cancers or other non-malignant diseases, as needed for individual patients, the researchers say.

“This study represents a success of multidisciplinary basic science, explaining how bioforces involving antigen recognition initiate TCR signaling through the T-cell membrane with potential for future translational impact,” says the study’s senior author, Ellis Reinherz, MD, Chief of the Laboratory of Immunobiology and Professor of Medicine in the Department of Medical Oncology at Dana-Farber and Harvard Medical School. “A special scientist such as Kristine Brazin with tireless persistence, focus and intellect was required to solve this mystery over more than a decade of research effort,” he added.

Source:

https://www.dana-farber.org/newsroom/news-releases/2018/study-uncovers-key-parts-of-mechanism-for-activating-t-cells-to-fight-cancer-and-other-diseases/

Tagged with:

About author

Related Articles