Xiaolei Su, PhD
Cards
Contact Info
Yale School of Medicine
333 Cedar St, PO BOX 208002, SHMC 425A
New Haven, CT 06520
United States
About
Titles
Associate Professor of Cell Biology
Biography
Dr. Xiaolei Su received initial scientific training at Peking University as an undergraduate. He obtained a Ph.D. degree at Harvard, where he investigated cytoskeleton dynamics under the mentorship of David Pellman. He joined Ron Vale's Lab at UCSF as a postdoc fellow and revealed that phase separation of membrane-associated proteins promotes T cell activation. Dr. Su started his own group at Yale in 2018. His current research focuses on membrane remodeling and membrane receptor signaling during immune responses. Dr. Su's team combined biochemical reconstitution with live cell imaging and animal model to understand how biomolecular condensation regulates immune signaling. They also investigated the molecular pathways underlying CAR T activation and designed CARs with new signaling functions to target blood, skin, colon, breast, and brain cancers.
Appointments
Cell Biology
Associate Professor on TermPrimary
Other Departments & Organizations
- Biochemistry, Quantitative Biology, Biophysics and Structural Biology (BQBS)
- Cancer Immunology
- Cell Biology
- Gold College Affiliates
- Molecular Cell Biology, Genetics and Development
- Yale Cancer Center
- Yale Center for Immuno-Oncology
- Yale Center for Systems and Engineering Immunology (CSEI)
- Yale Combined Program in the Biological and Biomedical Sciences (BBS)
Education & Training
- Postdoc
- University of California, San Francisco (2017)
- PhD
- Harvard University, Cell and Developmental Biology (2012)
- Student
- Physiology Course, Marine Biological Laboratory (2009)
- BS
- Peking University, Biological Sciences (2006)
Research
Overview
The cell membrane not only separates the intracellular space from the external environment, but also provides a platform for the receiving, processing and transduction of extracellular stimuli. The two-dimensional geometry, the interaction between proteins and lipids, and the local membrane curvature all converge to generate emergent properties of membrane-proximal signaling whereas the underlying mechanisms and functional consequences are not well understood. Immune receptor signaling represents a good example of this scenario. The highly dynamic membranes in the synapse and multiple ligand-receptor interaction pairs posted numerous exciting questions to explore in both basic biology and immunotherapy development.
Mechanism of CAR-T cell activation
The chimeric antigen receptor (CAR) enables T cells to specifically target and kill cancer cells. Despite of its success in clinical trials, the cellular mechanism of how CAR is activated by antigen and how activated CAR triggers downstream signaling pathways remains unclear. We have established a supported lipid bilayer system coupled with TIRF imaging for visualizing CAR signaling at high spatial and temporal resolutions. These enable my group to comprehensively investigate and manipulate the signaling pathway in both regular and CAR-T cells. We revealed a size-dependent mechanism explaining how antigen engagement triggers CAR activation, which solves a long-standing question in the CAR field. We also discovered that CAR induces an unstable synapse that has a disorganized pattern; moreover, CAR bypasses LAT, a key adaptor in the TCR pathway, to activate T cells. These knowledge in basic immune signaling guided us to design new CARs and engineer immune cells to improve the antitumor responses. Currently we are exploring the following questions:
- How is signaling amplified along the CAR pathway?
- How does phase separation affect CAR signaling?
- How to design CARs with improved antigen sensitivity?
Mast cell granule and anti-tumor function
Mast cells are among the least understood immune cells though they are widely distributed in tissues and communicate with a variety of immune and stroma cells either through direct contacts or secreted mediators. The cytoplasm of mast cells is filled up with granules that contain multiple mediators including bioactive chemicals, proteases, cytotoxic factors, chemokines, signaling lipids and glycans. Interestingly, many of these mediates remain in the granules even after their release into the extracellular space where there are no membranes wrapping around granules. The underlying biochemical mechanism is unclear. Functionally, mast cells were traditionally associated with inflammatory diseases including asthma and urticaria. We propose to repurpose the inflammatory role of mast cells for an anti-tumor function. This is expected to overcome some of the major hurdles preventing T cell-centered therapy for solid tumors. Currently we are exploring the following questions:
- How do mast cell extracellular granules maintain their structural and functional integrity?
- Can we program mast cells to target solid tumors through developing novel CARs?
Transcellular migration of leukocytes
During an immune response to pathogen infection, Leukocytes, which normally circulate in the vascular system, transmigrate through the endothelial layer to reach infected tissues and clear pathogens. Similarly, circulating metastatic cancer cells transmigrate through the endothelial layer to reach new colonization sites. In traditional views, transendothelial migration occurs at cell-cell junctions (paracellularly). However, recent evidence suggested the presence of transcellular migration, in which leukocytes or cancer cells penetrate through the endothelial cell to exit blood vessel. This transcellular process requires intimate interactions and bidirectional signaling between the invading and receiving cells, accompanied by highly coordinated remodeling of cytoskeleton and membrane systems. Currently we are exploring the following questions:
- What are the ligand-receptor pairs that mediate bi-directional signaling between endothelial cells and leukocytes?
- How do endothelial cells remodel their membranes to accommodate transcellular migration?
Medical Subject Headings (MeSH)
Research at a Glance
Yale Co-Authors
Publications Timeline
Research Interests
Longhui Zeng, PhD
Walker Fuchs
Receptors, Chimeric Antigen
Cell Membrane
Publications
Featured Publications
Size-dependent activation of CAR-T cells
Xiao Q, Zhang X, Tu L, Cao J, Hinrichs CS, Su X. Size-dependent activation of CAR-T cells. Science Immunology 2022, 7: eabl3995. PMID: 35930653, PMCID: PMC9678385, DOI: 10.1126/sciimmunol.abl3995.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsIntermembrane spacePlasma membraneIntracellular domainExtracellular domainMolecular mechanismsLarge isoformDownstream pathwaysT cell activationVariety of cancersCaR's extracellular domainAntigen engagementAntigen receptorSize differencesCell activationActivation of CARActivationMouse lymphoma modelCD45Antigen signalCellsLymphoma modelKinasePhosphorylationCD45RABCViral infectionPLCγ1 promotes phase separation of T cell signaling components
Zeng L, Palaia I, Šarić A, Su X. PLCγ1 promotes phase separation of T cell signaling components. Journal Of Cell Biology 2021, 220: e202009154. PMID: 33929486, PMCID: PMC8094118, DOI: 10.1083/jcb.202009154.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsTCR signal transductionT-cell receptor pathwayLiquid-like condensatesKey adaptor proteinLAT clusteringLAT complexSH2 domainAdaptor proteinPhosphatase CD45Signal transductionTCR pathwayPhospholipase Cγ1ERK activationProtein compositionBiophysical principlesPLCγ1Critical functionsReceptor pathwayPathwayLATMajor componentT cellsCellsActivationDephosphorylationRewired signaling network in T cells expressing the chimeric antigen receptor (CAR)
Dong R, Libby KA, Blaeschke F, Fuchs W, Marson A, Vale RD, Su X. Rewired signaling network in T cells expressing the chimeric antigen receptor (CAR). The EMBO Journal 2020, 39: e104730. PMID: 32643825, PMCID: PMC7429742, DOI: 10.15252/embj.2020104730.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsCentral supramolecular activation clusterEssential scaffold proteinT cell receptorSupramolecular activation clusterImmunological synapse formationAntigen receptorActin remodelingScaffold proteinMicrocluster formationDownstream signalingTCR signalingT cell activationSynapse formationCancer cellsSpecific cancer cellsCell receptorSignalingCAR activationT cellsCell activationCellsCAR-T cell activationNative T cellsPathwayActivation clusters
2023
The physical landscape of CAR-T synapse
Xiong Y, Libby K, Su X. The physical landscape of CAR-T synapse. Biophysical Journal 2023 PMID: 37715447, DOI: 10.1016/j.bpj.2023.09.004.Peer-Reviewed Original ResearchCitationsAltmetric
2022
SILAC Phosphoproteomics Reveals Unique Signaling Circuits in CAR‑T Cells and the Inhibition of B Cell-Activating Phosphorylation in Target Cells
Griffith AA, Callahan KP, King NG, Xiao Q, Su X, Salomon AR. SILAC Phosphoproteomics Reveals Unique Signaling Circuits in CAR‑T Cells and the Inhibition of B Cell-Activating Phosphorylation in Target Cells. Journal Of Proteome Research 2022, 21: 395-409. PMID: 35014847, PMCID: PMC8830406, DOI: 10.1021/acs.jproteome.1c00735.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsCD19 CAR T cellsChimeric antigen receptorRaji B cellsT cellsB cellsCAR T cell activityT cell activityB-cell malignanciesT cell receptor signalingCAR T cell signalingCell receptor signalingCD19-CARCell malignanciesT cell signalingCell activityReceptor signalingAntigen receptorLiquid chromatography-tandem mass spectrometryTarget cellsSignificant decreaseChromatography-tandem mass spectrometryTCR signalingReceptorsResponse of cellsCells
2021
Phase separation in immune signalling
Xiao Q, McAtee CK, Su X. Phase separation in immune signalling. Nature Reviews Immunology 2021, 22: 188-199. PMID: 34230650, PMCID: PMC9674404, DOI: 10.1038/s41577-021-00572-5.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsGene I proteinImmune Signaling PathwaysCyclic GMP-AMP synthaseSubstantial conformational changesNew biophysical principleGMP-AMP synthaseCell receptorB cell receptorCytosolic eventsSignal transductionImmune signalingSignaling pathwaysI proteinConformational changesLigand engagementDownstream adaptorsInterferon genesImmune receptorsBiophysical principlesLiquid-liquid phase separationFunctional consequencesT cell receptorPathogenic stimuliSpatial reorganizationOutstanding questions
2020
Surfing on Membrane Waves: Microvilli, Curved Membranes, and Immune Signaling
Orbach R, Su X. Surfing on Membrane Waves: Microvilli, Curved Membranes, and Immune Signaling. Frontiers In Immunology 2020, 11: 2187. PMID: 33013920, PMCID: PMC7516127, DOI: 10.3389/fimmu.2020.02187.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsMeSH KeywordsActin CytoskeletonAnimalsCarrier ProteinsCell LineCell MembraneCell ShapeCyclodextrinsCytokinesGlycocalyxHumansLymphocyte ActivationMembrane LipidsMembrane ProteinsMiceMicrofilament ProteinsMicroscopy, Electron, ScanningMicrovilliReceptors, Antigen, T-CellSignal TransductionStress, MechanicalSurface PropertiesSynaptosomesT-LymphocytesConceptsFunctional consequencesFinger-like membrane protrusionsT cell signalingSuper-resolution microscopyLocal membrane curvatureActin cytoskeletonMembrane protrusionsSignal transductionCell signalingMembrane curvatureCurved membranesImmune signalingBiochemical activityUnique compartmentLymphocyte microvilliMicrovillus formationCell typesLocal membraneCytoskeletonSignalingMicrovilliMembraneBody of evidenceMembrane wavesImportant roleImaging Chimeric Antigen Receptor (CAR) Activation
Libby KA, Su X. Imaging Chimeric Antigen Receptor (CAR) Activation. Methods In Molecular Biology 2020, 2111: 153-160. PMID: 31933206, DOI: 10.1007/978-1-0716-0266-9_13.Peer-Reviewed Original ResearchCitationsMeSH Keywords and Concepts
2019
A composition-dependent molecular clutch between T cell signaling condensates and actin
Ditlev JA, Vega AR, Köster DV, Su X, Tani T, Lakoduk AM, Vale RD, Mayor S, Jaqaman K, Rosen MK. A composition-dependent molecular clutch between T cell signaling condensates and actin. ELife 2019, 8: e42695. PMID: 31268421, PMCID: PMC6624021, DOI: 10.7554/elife.42695.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and Concepts
2016
Phase separation of signaling molecules promotes T cell receptor signal transduction
Su X, Ditlev JA, Hui E, Xing W, Banjade S, Okrut J, King DS, Taunton J, Rosen MK, Vale RD. Phase separation of signaling molecules promotes T cell receptor signal transduction. Science 2016, 352: 595-599. PMID: 27056844, PMCID: PMC4892427, DOI: 10.1126/science.aad9964.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsT cell receptor (TCR) signal transductionHuman Jurkat T cellsActin filament assemblySubmicrometer-sized clustersReceptor signal transductionT cell receptor activationProtein phase separationJurkat T cellsCell receptor activationCell surface receptorsTCR phosphorylationActin regulatorsActin assemblySignal transductionFilament assemblyBiochemical compartmentsFunctional consequencesSurface receptorsModel membranesReceptor activationAssemblyActivationTransductionKinasePhosphorylation
Academic Achievements and Community Involvement
honor Lion Heart Pilot Award
Yale University AwardYale New Haven Hospital and Yale Cancer CenterDetails01/01/2024United Stateshonor Pershing Square Sohn Prize for Young Investigators in Cancer Research
Regional AwardPershing Square Sohn Cancer Research Alliance (PSSCRA)Details05/12/2023United Stateshonor Gabrielle's Angel Foundation Medical Research Award
National AwardGabrielle's Angel FoundationDetails02/01/2023United Stateshonor American Cancer Society Research Scholar Grant
National AwardAmerican Cancer SocietyDetails01/01/2022United Stateshonor Human Frontier Science Program Early-Career Research Grant
National AwardHuman Frontier Science ProgramDetails12/01/2021United States
Links & Media
News
- February 28, 2024
Grants Awarded at YCC • 2024
- May 18, 2023
Xiaolei Su Wins Pershing Square Sohn Prize for Cancer Research
- May 17, 2023Source: Pershing Square Sohn Cancer Research Alliance
Yale Scientist Receives Pershing Square Sohn Prize for Young Investigators in Cancer Research
- May 07, 2023
Meet Our Speakers: Dr. Gillian Griffiths
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Yale School of Medicine
333 Cedar St, PO BOX 208002, SHMC 425A
New Haven, CT 06520
United States