Xiaolei Su, PhD
Research & Publications
Biography
News
Research Summary
Membrane, Immune Signaling and Cancer Immunity
The Su Lab studies membrane remodeling and membrane-proximal signal transduction during immune responses. Using combined approaches of biochemical reconstitution, high resolution microscopy, cell engineering, and animal models, we aim to understand how spatial and temporal organization of membrane proteins and lipids regulates immune cell activation. In particular, we are interested in revealing the role of biomolecular condensation in immune signaling. These knowledges are leveraged to the development of new strategies and tools for cancer immunotherapy.
We are recruiting postdocs, students, and postbacs who are excited about membrane signaling and immunology. See more details on our website www.sulab.net.
Extensive Research Description
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?
Research Interests
Biophysics; Cell Membrane; Cell Biology; Leukemia; Mast Cells; Melanoma; Endothelial Cells; Adaptive Immunity; Transendothelial and Transepithelial Migration; Receptors, Chimeric Antigen
Public Health Interests
Cancer
Selected Publications
- Size-dependent activation of CAR-T cellsXiao 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.
- PLCγ1 promotes phase separation of T cell signaling componentsZeng 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.
- Rewired 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.
- Imaging CAR-T Synapse as a Quality Control for CAR EngineeringXiao Q, Su X. Imaging CAR-T Synapse as a Quality Control for CAR Engineering 2023, 2654: 503-512. PMID: 37106204, DOI: 10.1007/978-1-0716-3135-5_33.
- Anti-tumor Efficacy of CD19 CAR-T in a Raji B Cell Xenografted Mouse ModelXiao Q, Su X. Anti-tumor Efficacy of CD19 CAR-T in a Raji B Cell Xenografted Mouse Model Bio-protocol 2023, 13: e4655. PMID: 37113332, PMCID: PMC10127058, DOI: 10.21769/bioprotoc.4655.
- SILAC Phosphoproteomics Reveals Unique Signaling Circuits in CAR‑T Cells and the Inhibition of B Cell-Activating Phosphorylation in Target CellsGriffith 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.
- Phase separation in immune signallingXiao 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.
- Surfing on Membrane Waves: Microvilli, Curved Membranes, and Immune SignalingOrbach 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.
- Imaging Chimeric Antigen Receptor (CAR) ActivationLibby KA, Su X. Imaging Chimeric Antigen Receptor (CAR) Activation 2020, 2111: 153-160. PMID: 31933206, DOI: 10.1007/978-1-0716-0266-9_13.
- A composition-dependent molecular clutch between T cell signaling condensates and actinDitlev 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.
- Mechanisms of Chimeric Antigen Receptor (CAR) Signaling during T Cell ActivationSu X, Vale R. Mechanisms of Chimeric Antigen Receptor (CAR) Signaling during T Cell Activation Biophysical Journal 2018, 114: 107a-108a. DOI: 10.1016/j.bpj.2017.11.625.
- Differential LAT Microcluster Composition and ACTIN-Dependent Movement at the Immunological Synapse CenterVega A, Ditlev J, Koster D, Su X, Vale R, Mayor S, Rosen M, Jaqaman K. Differential LAT Microcluster Composition and ACTIN-Dependent Movement at the Immunological Synapse Center Biophysical Journal 2018, 114: 201a. DOI: 10.1016/j.bpj.2017.11.1123.
- Reconstitution of TCR Signaling Using Supported Lipid BilayersSu X, Ditlev JA, Rosen MK, Vale RD. Reconstitution of TCR Signaling Using Supported Lipid Bilayers 2017, 1584: 65-76. PMID: 28255696, PMCID: PMC5633369, DOI: 10.1007/978-1-4939-6881-7_5.
- Abstract B101: Mechanism of T cell activation by phase separationSu X, Ditlev J, Hui E, Rosen M, Vale R. Abstract B101: Mechanism of T cell activation by phase separation Cancer Immunology Research 2016, 4: b101-b101. DOI: 10.1158/2326-6066.imm2016-b101.
- Phase separation of signaling molecules promotes T cell receptor signal transductionSu 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.
- Abstract A087: Phase separation of signaling molecules promotes T cell receptor signal transductionSu X, Ditlev J, Hui E, Banjade S, Okrut J, Taunton J, Rosen M, Vale R. Abstract A087: Phase separation of signaling molecules promotes T cell receptor signal transduction Cancer Immunology Research 2016, 4: a087-a087. DOI: 10.1158/2326-6074.cricimteatiaacr15-a087.
- Microtubule-sliding activity of a kinesin-8 promotes spindle assembly and spindle-length controlSu X, Arellano-Santoyo H, Portran D, Gaillard J, Vantard M, Thery M, Pellman D. Microtubule-sliding activity of a kinesin-8 promotes spindle assembly and spindle-length control Nature Cell Biology 2013, 15: 948-957. PMID: 23851487, PMCID: PMC3767134, DOI: 10.1038/ncb2801.
- Novel Roles of Kinesin-8 in Organizing Mitotic SpindlesSu X, Pellman D. Novel Roles of Kinesin-8 in Organizing Mitotic Spindles Biophysical Journal 2012, 102: 702a. DOI: 10.1016/j.bpj.2011.11.3812.
- Mechanisms Underlying the Dual-Mode Regulation of Microtubule Dynamics by Kip3/Kinesin-8Su X, Qiu W, Gupta ML, Pereira-Leal JB, Reck-Peterson SL, Pellman D. Mechanisms Underlying the Dual-Mode Regulation of Microtubule Dynamics by Kip3/Kinesin-8 Molecular Cell 2011, 43: 751-763. PMID: 21884976, PMCID: PMC3181003, DOI: 10.1016/j.molcel.2011.06.027.
- Quantitative Test for Mirror Symmetry Relationship between Sister CellsRafelski S, Schroder J, Torrealba C, Mueller M, Su X, Guo M, Marshall W, Brun L, Oakes P, Janvore J, Hu Q, Hou J. Quantitative Test for Mirror Symmetry Relationship between Sister Cells Biophysical Journal 2010, 98: 430a. DOI: 10.1016/j.bpj.2009.12.2329.