Scientists have developed a new method to faster and more accurately predict which antigens will lead to a strong immune response. This could help researchers develop more effective cancer immunotherapies.
A cells secrets can be revealed by its surface. It is decorated with tens to hundreds of thousands of molecules that help immune cells determine friend from foe. Some of those protruding molecules are antigens that trigger the immune system to attack. However, it can be difficult for scientists to identify those antigens, which often vary across individuals, in the molecular forest.
A team of Stanford scientists has developed a new method to faster and more accurately predict which antigens will lead to a strong immune response. Their approach could help researchers develop more effective cancer immunotherapies. The study was led by Polly Fordyce, an Institute Scholar at Sarafan ChEM-H, and will be reported today (September 5, 2022) in the journal Nature Methods.
T cells, a class of immune cells, crawl along and squish past other cells as they patrol the body. They use T cell receptors to molecularly read peptides, or short pieces of proteins which are cradled within larger proteins called major histocompatibility complexes (pMHCs) that project from cell surfaces. Healthy host cells display an array of pMHCs that do not trigger an immune response. However, once T cells recognize disease-indicating peptides, they become activated to find and kill cells bearing these foreign signatures. Understanding how T cells sensitively differentiate these antigenic peptides from host peptides to avoid mistakenly killing host cells has long been a mystery.
A T cell can detect a single antigenic peptide amongst a sea of 10,000 or 100,000 non-antigenic peptides being displayed on cell surfaces, said Fordyce, assistant professor of bioengineering and of genetics.
The key to selectivity is in the T cell crawl. T cells sliding puts stress on the bonds between receptors and peptides, and most of the time, that extra stress is enough to break that bond. But sometimes, it has the opposite effect. Chris Garcia, co-author of the study and professor of molecular and cellular physiology and of structural biology, and others had previously shown that the most antigenic peptides are those whose interactions with T cell receptors grow stronger in response to sliding.
Its kind of like a Chinese finger trap, said Fordyce. When you pull a bit at the receptor-antigen interaction, the binding actually lasts longer.
Identifying the best antigen-receptor pairs requires simultaneously applying that sliding, or shear, force between a peptide and a T cell and measuring T cell activation. Ideally, this would be done thousands of times to get repeatable data for many possible peptide/T cell receptor pairs. However, existing methods are time-intensive and can result in measuring only one peptide with hundreds of T cells in a day.
Postdoctoral scholar Yinnian Feng, the studys first author, developed a trick that allows the team to measure 20 unique peptides interacting with thousands of T cells in less than five hours.
To make a simplified system that mimics cells with dangling peptides, they constructed small spherical beads from a material that expands upon heating and attached a few molecules of a given peptide-studded pMHC to their surfaces. After depositing a T cell atop each bead and waiting long enough for receptors to bind to the peptides, they then very slightly heated the bead. The beads expansion increases the distance between tether points, and the corresponding stretching of the T cell mimics the force it would experience sliding along cells in the body. After exerting that force, the team then measured how active the T cells were.
They could do hundreds of individual experiments in parallel by using beads that are each labeled with a unique color, making it possible to track multiple different pMHCs. They took two sets of pictures tiling across each slide after each run: one set that tells them which pMHC a given bead is displaying and another that tells them how active each T cell atop that bead is. Cross-referencing those images tells them which antigens led to the strongest T cell responses.
In this demonstration of their platform, the research team showed, with 21 unique peptides, that their results confirmed known activating and non-activating peptides for one T cell receptor and uncovered a previously unknown antigen that induced a strong T cell response. Working with the Garcia lab, they have also already begun to address a challenge in immunotherapy: the T cell receptors that form the highest affinity interactions with antigens in the lab are often also activated by non-antigenic peptides in the body. This is a dangerous side effect that leads to the killing of healthy cells.
Using their technology, the team of researchers characterized T cell receptors engineered to specifically recognize tumor antigens without off-target reactivity. In future work, they plan to build libraries of over 1,000 peptides to uncover novel antigens.
The scientists hope that this approach, which is quick and requires few cells, or an optimized form of it could one day be used to improve personalized immunotherapies.
This platform can help improve efforts to engineer T cells that specifically target cancer cells, as well as determine which antigens are capable of potently activating a patients own T cells to more effectively target cancer cells, said Fordyce.
Reference: Bead-based method for high-throughput mapping of the sequence- and force-dependence of T cell activation 5 September 2022, Nature Methods.DOI: 10.1038/s41592-022-01592-2
Fordyce is a member of Stanford Bio-X, SPARK, and the Wu Tsai Neurosciences Institute, and is a Chan Zuckerberg Biohub investigator. Garcia is a member of Stanford Bio-X, the Stanford Cancer Institute, the Wu Tsai Neurosciences Institute, and a Howard Hughes Medical Institute investigator.
Xiang Zhao and Adam K. White are also authors of the paper.
The work was funded by a Stanford Bio-X Interdisciplinary Initiatives seed grant and the National Institutes of Health.
Go here to see the original:
More Effective Cancer Immunotherapy: Stanfords New Method To Find Antigens That Trigger Specific Immune Cells - SciTechDaily
- Distinguished investigator brings expertise in genetics and cell biology to Texas A&M AgriLife - AgriLife Today - October 26th, 2024 [October 26th, 2024]
- Institute of Molecular and Cell Biology (IMCB) - Agency for Science, Technology and Research (A*STAR) - October 13th, 2024 [October 13th, 2024]
- Joseph Gall, father of modern cell biology, dead at 96 - Carnegie Institution for Science - September 15th, 2024 [September 15th, 2024]
- A dual role of ERGIC-localized Rabs in TMED10-mediated unconventional protein secretion - Nature.com - June 27th, 2024 [June 27th, 2024]
- Yoshihiro Yoneda Appointed President of the International Human Frontier Science Program Organization - PR Newswire - June 27th, 2024 [June 27th, 2024]
- A new way to measure ageing and disease risk with the protein aggregation clock - EurekAlert - June 18th, 2024 [June 18th, 2024]
- How Flow Cytometry Spurred Cell Biology - The Scientist - June 18th, 2024 [June 18th, 2024]
- Building Cells from the Bottom Up - The Scientist - June 18th, 2024 [June 18th, 2024]
- From Code to Creature - The Scientist - June 18th, 2024 [June 18th, 2024]
- Adding intrinsically disordered proteins to biological ageing clocks - Nature.com - May 24th, 2024 [May 24th, 2024]
- Advancing Cell Biology and Cancer Research via Cell Culture and Microscopy Imaging Techniques - Lab Manager Magazine - May 24th, 2024 [May 24th, 2024]
- Study explores how different modes of cell division evolved in close relatives of fungi and animals - News-Medical.Net - May 24th, 2024 [May 24th, 2024]
- Solving the Wnt nuclear puzzle - Nature.com - May 24th, 2024 [May 24th, 2024]
- Prof. Jay Shendure Joins Somite Therapeutics as Scientific Co-founder - BioSpace - May 24th, 2024 [May 24th, 2024]
- One essential step for a germ cell, one giant leap for the future of reproductive medicine - EurekAlert - May 24th, 2024 [May 24th, 2024]
- May: academy-medical-sciences | News and features - University of Bristol - May 24th, 2024 [May 24th, 2024]
- Universal tool for tracking cell-to-cell interactions - ASBMB Today - May 24th, 2024 [May 24th, 2024]
- Close Encounters of Skin and Nerve Cells - The Scientist - April 15th, 2024 [April 15th, 2024]
- OrthoID: Decoding Cellular Conversations with Cutting-Edge Technology - yTech - April 15th, 2024 [April 15th, 2024]
- Impact of aldehydes on DNA damage and aging - EurekAlert - April 15th, 2024 [April 15th, 2024]
- Redefining Cell Biology: Nondestructive Genetic Insights With Raman Spectroscopy - SciTechDaily - March 29th, 2024 [March 29th, 2024]
- Scientists Unravel the Unusual Cell Biology Behind Toxic Algal Blooms - SciTechDaily - March 19th, 2024 [March 19th, 2024]
- Ancient retroviruses played a key role in the evolution of vertebrate brains - EurekAlert - February 21st, 2024 [February 21st, 2024]
- Singapore scientists uncover a crucial link between cholesterol synthesis and cancer progression - EurekAlert - February 4th, 2024 [February 4th, 2024]
- Scientists uncover a way to "hack" neurons' internal clocks to speed up brain cell development - News-Medical.Net - February 4th, 2024 [February 4th, 2024]
- First atomic-scale 'movie' of microtubules under construction, a key process for cell division - EurekAlert - February 4th, 2024 [February 4th, 2024]
- Small RNAs take on the big task of helping skin wounds heal better and faster with minimal scarring - EurekAlert - February 4th, 2024 [February 4th, 2024]
- Shengjie Feng channels the powers of cryogenic electron microscopy - Newswise - January 19th, 2024 [January 19th, 2024]
- Study pinpoints breast cancer cells-of-origi - EurekAlert - January 19th, 2024 [January 19th, 2024]
- New analysis of cancer cells identifies 370 targets for smarter, personalized treatments - News-Medical.Net - January 19th, 2024 [January 19th, 2024]
- EU funding for pioneering research on the treatment of gliomas - EurekAlert - January 19th, 2024 [January 19th, 2024]
- The future of mRNA biology and AI convergence - Drug Target Review - December 22nd, 2023 [December 22nd, 2023]
- The future of artificial breast milk, according to one lab - Quartz - December 22nd, 2023 [December 22nd, 2023]
- Shedding new light on the hidden organization of the cytoplasm - News-Medical.Net - December 22nd, 2023 [December 22nd, 2023]
- Bugs that help bugs: How environmental microbes boost fruit fly reproduction - EurekAlert - December 22nd, 2023 [December 22nd, 2023]
- Cells Move in Groups Differently Than They Do When Alone - NYU Langone Health - December 14th, 2023 [December 14th, 2023]
- Cells move in groups differently than they do when alone - EurekAlert - December 14th, 2023 [December 14th, 2023]
- Seattle Hub for Synthetic Biology plans to transform cells into tiny recording devices - GeekWire - December 14th, 2023 [December 14th, 2023]
- Virginia Tech and Weizmann Institute of Science tackle cell ... - Virginia Tech - October 16th, 2023 [October 16th, 2023]
- Vast diversity of human brain cell types revealed in trove of new ... - Spectrum - Autism Research News - October 16th, 2023 [October 16th, 2023]
- Singamaneni to develop advanced protein imaging method - The ... - Washington University in St. Louis - October 16th, 2023 [October 16th, 2023]
- Researchers find certain cancers can activate 'enhancer' in the ... - University of Toronto - October 16th, 2023 [October 16th, 2023]
- 2023 Hettleman Prizes awarded to five exceptional early-career ... - UNC Research - October 16th, 2023 [October 16th, 2023]
- Faeth Therapeutics Announces National Academy of Medicine ... - BioSpace - October 16th, 2023 [October 16th, 2023]
- From Migrant Farm Worker to Duke Scientist, Everardo Macias ... - Duke University School of Medicine - October 16th, 2023 [October 16th, 2023]
- Finding the golden ticket? Cyclin T1 is required for HIV-1 latency ... - Fred Hutch News Service - October 16th, 2023 [October 16th, 2023]
- Spermidine May Improve Egg Health and Fertility - Lifespan.io News - October 16th, 2023 [October 16th, 2023]
- Molecule discovered that grows bigger and stronger muscles - Earth.com - October 16th, 2023 [October 16th, 2023]
- SGIOY: 3 Biotech Stocks With Potential Future Gains - StockNews.com - October 16th, 2023 [October 16th, 2023]
- Association for Molecular Pathology Publishes Best Practice ... - Technology Networks - October 16th, 2023 [October 16th, 2023]
- A new cell type with links to gastric cancer steps up for its mugshot - Fred Hutch News Service - October 16th, 2023 [October 16th, 2023]
- Programmed cell death may be 1.8 billion year - EurekAlert - October 16th, 2023 [October 16th, 2023]
- New study confirms presence of flesh-eating and illness-causing ... - Science Daily - October 16th, 2023 [October 16th, 2023]
- New Institute for Immunologic Intervention (3i) at the Hackensack ... - Hackensack Meridian Health - October 16th, 2023 [October 16th, 2023]
- Post-doctoral Fellow in Cancer Biology in the Department of ... - Times Higher Education - October 16th, 2023 [October 16th, 2023]
- Scientists uncover key enzymes involved in bacterial pathogenicity - News-Medical.Net - October 16th, 2023 [October 16th, 2023]
- B cell response after influenza vaccine in young and older adults - EurekAlert - October 16th, 2023 [October 16th, 2023]
- Post-doctoral researcher in yeast cell biology job with UNIVERSITY ... - Times Higher Education - April 8th, 2023 [April 8th, 2023]
- expert reaction to study looking at creating embryo-like structures ... - Science Media Centre - April 8th, 2023 [April 8th, 2023]
- UCF Bone Researcher Receives National Recognition - UCF - April 8th, 2023 [April 8th, 2023]
- PhenomeX to Participate in American Association of Cancer ... - BioSpace - April 8th, 2023 [April 8th, 2023]
- Inland Empire stem-cell therapy gets $2.9 million booster - UC Riverside - April 8th, 2023 [April 8th, 2023]
- New finding in roundworms upends classical thinking about animal cell differentiation - News-Medical.Net - April 8th, 2023 [April 8th, 2023]
- Biology's unsolved chicken-or-egg problem: Where did life come from? - Big Think - April 8th, 2023 [April 8th, 2023]
- Azacitidine in Combination With Trametinib May Be Effective for ... - The ASCO Post - April 8th, 2023 [April 8th, 2023]
- Researchers clear the way for well-rounded view of cellular defects - Phys.org - April 8th, 2023 [April 8th, 2023]
- We were dancing around the lab cellular identity discovery has potential to impact cancer treatments - Newswise - April 8th, 2023 [April 8th, 2023]
- Environmental stressors' effect on gene expression explored in lecture - Environmental Factor Newsletter - April 8th, 2023 [April 8th, 2023]
- RNA therapy restores gene function in monkeys modeling ... - Spectrum - Autism Research News - April 8th, 2023 [April 8th, 2023]
- Traumatic brain injury interferes with immune system cells' recycling ... - Science Daily - April 8th, 2023 [April 8th, 2023]
- Lab-grown fat could give cultured meat real flavor and texture - EurekAlert - April 8th, 2023 [April 8th, 2023]
- Researchers reveal mechanism of polarized cortex assembly in migrating cells - Phys.org - April 8th, 2023 [April 8th, 2023]
- Probing Selfish Centromeres Unveils an Evolutionary Arms Race - The Scientist - April 8th, 2023 [April 8th, 2023]
- Meet the 2023 Outstanding Graduating Students - UMaine News ... - University of Maine - April 8th, 2023 [April 8th, 2023]
- The Worlds Sexiest Fragrance Unveiled, But Its Not For You - Revyuh - April 8th, 2023 [April 8th, 2023]
- City of Hope appoints John D. Carpten, Ph.D., as director of its ... - BioSpace - April 8th, 2023 [April 8th, 2023]
- Modernized Algorithm Predicts Drug Targets for SARS-CoV-2, Other ... - GenomeWeb - April 8th, 2023 [April 8th, 2023]
- BU researcher wins $3.9 million NIH grant to develop novel therapeutic modalities for Alzheimer's - News-Medical.Net - April 8th, 2023 [April 8th, 2023]
- Providing critical insights for animal development - HKU biologists ... - EurekAlert - April 8th, 2023 [April 8th, 2023]
- Students Express Frustrations About the Middle Class Scholarship - The Triton - April 8th, 2023 [April 8th, 2023]