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Enfu Hui

Research

Immune checkpoint receptors critically regulate immune response to infections, cancer, and other diseases. While immune checkpoint receptors help maintain immune homestasis, certain diseases such as cancer can hijack these receptors to evade the destruction by the immune system. Immunotherapies that target immune checkpoint receptors have shown great promise in treating varying subset of patients with certain cancers. However, little is known about the fundamental mechanisms of immune checkpoint receptors, limiting the abilities of researchers to develop new and effective immunotherapies.

We study the mechanisms of immune checkpoint receptors at the interface of biophysics, biochemistry, cell biology and immunology. We utilize a unique combination of proteomics, membrane reconstitution, imaging, and conventional immunological approaches. We revealed the distinct SHP1/SHP2 binding preferences of PD1 and BTLA (JCB, 2020) and the underlying biochemical mechanism (eLife, 2021). Moreover, we demonstrated cis-interactions as a novel mechanism in regulating or mediating immune checkpoint signaling. Cis-PDL1:CD80 (B7-1) interaction represses PD1 and CTLA4 inhibitory signaling while preserving CD28 stimulatory signaling (Immunity, 2019). Cis-B7:CD28 interaction at invaginated synaptic membranes activates CD28 to promote anti-tumor activity of CD8+ T cells (Immunity, 2023). Conversely, CTLA4 depletes T-cell-associated CD80 and CD86 through cis-endocytosis to restrict T cell autostimulation (JEM, 2023). Our mechanistic studies could lead to the development of novel biomarkers and drug targets of immunotherapies.

Select Publications

  • Zhao Y, Caron C, Chan YY, Lee CK, Xu X, Zhang J, Masubuchi T, Wu C, Bui JD, Hui E. Cis-B7:CD28 Interactions at Invaginated Synaptic Membranes Activate CD28 and Promote T Cell Function and Anti-Tumor Immunity. Immunity. 2023; In press.
  • Xu X, Dennett P, Zhang J, Sherrard A, Zhao Y, Masubuchi T, Bui JD, Chen X, Hui E. CTLA4 depletes T cell endogenous and trogocytosed B7 ligands via cis-endocytosis. J Exp Med. 2023;220(7). Epub 20230412. doi: 10.1084/jem.20221391. PubMed PMID: 37042938.
  • Xu X, Masubuchi T, Cai Q, Zhao Y, Hui E. Molecular features underlying differential SHP1/SHP2 binding of immune checkpoint receptors. Elife. 2021;10. Epub 20211104. doi: 10.7554/eLife.74276. PubMed PMID: 34734802; PMCID: PMC8631942.
  • 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;219(6). doi: 10.1083/jcb.201905085. PubMed PMID: 32437509; PMCID: PMC7265324.
  • 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 20191119. doi: 10.1016/j.immuni.2019.11.003. PubMed PMID: 31757674; PMCID: PMC6935268.
  • 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. doi: 10.1016/j.celrep.2018.06.054. PubMed PMID: 29996099; PMCID: PMC6093302.

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 before joining the School of Biological Sciences at UCSD in July 2016. He was selected as a Searle Scholar, a Pew Scholar and a recipient of the R37 MERIT Award to early stage investigators from the National Cancer Institute.

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