Xiaolei Su, PhD
Research & Publications
Biography
News
Research Summary
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, and cell engineering, we aim to understand how spatial and temporal organization of membrane proteins and lipids regulates immune cell activation. These knowledges are leveraged to the development of new strategies and tools for cancer immunotherapy.
Extensive Research Description
The cell membrane not only separates the intracellular space from the external environment, but also provides a platform for the processing and transduction of inter- or intra-cellular signals. 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 are not well understood. The T cell receptor (TCR) pathway represents a good example of this scenario. Although major components in the pathway have been identified, it remains unclear how individual components assemble and coordinate to build up a pathway for effectively receiving and amplifying signals from pathogenic antigens. The goal of our research program is to understand the general principals of membrane-proximal signaling under the biological context of T cell activation and other immune response processes.
How does phase separation regulate lipid signaling?
Our previous work identified T cell microclusters as phase separated structures driven by multivalent protein-protein interactions. These microclusters display liquid-like properties and contain the capability of organizing molecules to promote biochemical reactions such as actin polymerization. Beyond that, T cell microclusters reside underneath cell membranes. It remains totally unclear how these proteinaceous structures interact with lipids and regulating lipid metabolism. Questions we are interested in addressing includes:
- How do T cell microclusters regulate PIP2 turnover?
- How do charged lipids regulate T cell signaling?
- Mechanisms of leukemia-associated mutations in phospholipase C gamma
How does chimeric antigen receptor (CAR) activate T cells?
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 and how activated CAR triggers downstream signaling pathways remains unclear. The domain structure of CAR is very different from the endogenous T cell receptor (TCR), which raises the question of whether CAR activates T cells in a similar mechanism to TCR or not, and how the T cell signaling network accommodates a synthetic receptor. From the clinical side, so far major challenges of CAR-T cell therapy reside in poor infiltration, low persistency, frequent relapse, and severe side effects (cytokine storm and neurotoxicity). Understanding CAR signaling will provide clues to designing improved CARs for cancer therapy.
We have established a supported lipid bilayer system together with TIRF imaging for visualizing CAR signaling at high spatial and temporal resolutions. We are currently exploring the following questions:
- How is signaling amplified along the CAR pathway?
- How does phase separation affect CAR signaling?
- How to engineer CAR signaling for targeting solid tumors?
Research Interests
Biophysics; Cell Membrane; Cell Biology; Leukemia; Melanoma; Adaptive Immunity; 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.
- 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.