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Enfu Hui

Research

Ideally, the immune system identifies tumors as threatening elements and deploys immune cells (T cells) to find and kill them. However, many tumor cells have evolved to employ a protein called PD-L1 to blind T cells from carrying out their functions and evade immune defenses. PD-L1 protects tumor cells by activating a "molecular brake" or “checkpoints” known as PD-1 to stop T cells. Remarkably, drugs that block PD-1 or its ligand PD-L1 have proven to release the PD-1 brake from T cells, and demonstrated unprecedented clinical activities in a variety of human cancers. Still, durable response is limited to a small subset of cancer patients. Identification of reliable predictive biomarkers, and targeting other immune checkpoints, either alone or in combination with PD-1 inhibitors, hold the promise of extending the therapy to more tumor types and a larger populations of patients. However, these efforts are slowed down by the incomplete molecular understanding of immune checkpoints.

We are a group of biochemists and cell biologists aiming to dissect the mechanisms of immune checkpoints, using cell-free membrane reconstitution, time-resolved live cell microscopy and cutting-edge cell biology approaches. We recently uncovered two novel aspects of PD-L1/PD-1 signaling. Intracellularly, we showed that the T cell costimulatory receptor CD28 is a primary target of PD-1 associated phosphatases. Extracellularly, we discovered that PD-L1, a key weapon of tumor cells, can be neutralized in cis by PD-1 expressed on the same cells. Now, we will continue to elucidate the PD-1 signaling pathway by identification of novel regulators and targets of PD-1. In addition, we are investigating whether and how additional immune brakes operate in conjunction with PD-1 to “turn off” T cell activity. We will identify the triggering molecules that turn these brakes on, and signal transducers these brakes recruit to suppress the immune response. Our findings could lead to the development of novel biomarkers and drug targets of cancer immunotherapy.

Select Publications

  • Xu X, Hou B, Fulzele A, Masubuchi T, Zhao Y, Wu Z, Hu Y, Jiang Y, Ma Y, Wang H, Bennett EJ, Fu G, Hui E. PD-1 and BTLA regulate T cell signaling differentially and only partially through SHP1 and SHP2. J Cell Biol. 2020 Jun 01; 219(6). PMID: 32437509
  • Zhao Y, Lee CK, Lin CH, Gassen RB, Xu X, Huang Z, Xiao C, Bonorino C, Lu LF, Bui JD, Hui E. PD-L1:CD80 Cis-Heterodimer Triggers the Co-stimulatory Receptor CD28 While Repressing the Inhibitory PD-1 and CTLA-4 Pathways. Immunity. 2019;51(6):1059-73 e9. Epub 2019/11/24. doi: 10.1016/j.immuni.2019.11.003. PubMed PMID: 31757674; PMCID: PMC6935268.
  • Hui E. Immune checkpoint inhibitors. J Cell Biol. 2019 03 04; 218(3):740-741. PMID: 30760493.
  • Hui E. Understanding T cell signaling using membrane reconstitution. Immunol Rev. 2019 09; 291(1):44-56. PMID: 31402497.
  • Zhao Y, Harrison DL, Song Y, Ji J, Huang J, Hui E. Antigen-Presenting Cell-Intrinsic PD-1 Neutralizes PD-L1 in cis to Attenuate PD-1 Signaling in T Cells. Cell Rep. 2018;24(2):379-90 e6. Epub 2018/07/12. doi: 10.1016/j.celrep.2018.06.054. PubMed PMID: 29996099.
  • Hui E, Cheung J, Zhu J, Su X, Taylor MJ, Wallweber HA, Sasmal DK, Huang J, Kim JM, Mellman I, Vale RD. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science. 2017;355(6332):1428-33. PubMed PMID: 28280247.
  • Hui E, Vale RD. In vitro membrane reconstitution of the T-cell receptor proximal signaling network. Nat Struct Mol Biol. 2014 Feb; 21(2):133-42. PMID: 24463463.

Biography

Enfu Hui obtained his Ph.D. in 2009 from UW Madison. He then completed his postdoctoral training at UCSF as a fellow of the Leukemia & Lymphoma Society. He joined the Division of Biological Sciences at UCSD in July 2016 and was named as a Searle Scholar and Pew Scholar.