Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity

C.E. CREDITS: P.A.C.E. CE | Florida CE
Speakers
  • Instructor, Department of Molecular and Cellular Oncology
    Biography
      Dr. Li earned his Ph.D. degree in the Department of Pharmacology at the University of Medicine & Dentistry of New Jersey (UMDNJ) in 2007. Following graduation, he joined Dr. Mien-Chie Hung's lab at U.T. M.D. Anderson Cancer Center as a postdoctoral fellow. He was later appointed to Instructor at MD Anderson. His research lies in understanding the regulatory mechanisms of PD-L1 for the identification of novel therapeutic targets, enhancing the efficacy and safety of immunotherapy. In addition, he has tremendous interest in studying breast cancer metastasis mechanisms, aiming to develop novel therapeutic strategies. Another focus of his research is on dissecting the PARP inhibitor.

    Abstract:

    The success of immune checkpoint blockade adds a new therapeutic category to the cancer therapy repertoire. Despite efforts made on cancer cell and immune cell interaction, how cancer cells initiate immune escape is less understood. Here we reveal PD-L1’s immunosuppression activity is stringently modulated by the spatial restraints between ubiquitination and N-linked glycosylation. We identified GSK3beta as a novel PD-L1 interacting protein capable of inducing phosphorylation dependent proteasome degradation. The essence of PD-L1 N192, N200 and N219 glycosylation suggests it antagonizes GSK3beta binding. In this regard, only non-glycosylated PD-L1 forms a complex with GSK3beta and beta-TrCP. More importantly, activation of GSK3beta-mediated PD-L1 degradation by TKI can reduce membrane PD-L1 expression and thereby enhance anti-tumor immunity. To test T cell-mediated cancer cell killing in vitro, we employed a time lapse microscopy, IncuCyte, to monitor RFP-tagged BT549 cells and activated PBMC interaction over a five day period. Massive cancer cell death was observed in glycosylation deficient cancer cells, suggesting glycosylation of PD-L1 is required for its immunosuppression. Together, our results link ubiquitination and glycosylation pathways with stringent regulation of PD-L1, proposing a new therapeutic strategy to enhance cancer immune therapy efficacy.

    Learning Objectives:

    • Molecular mechanism of PD-L1 regulation in cancer cells
    • Immunosuppressive nature of triple negative breast cancer
    • Using an in vitro co-culture system to analyze T cell-mediated cancer cell killing effect

    Show Resources
    You May Also Like
    AUG 27, 2019 09:00 AM PDT
    C.E. CREDITS
    AUG 27, 2019 09:00 AM PDT
    DATE: August 27, 2019 TIME: 9:00am PDT, 12:00pm EDT Immunotherapies targeting PD-1 or PD-L1 have proven remarkably effective for treating cancer in some patients, with considerabl...
    SEP 05, 2019 04:00 PM CEST
    C.E. CREDITS
    SEP 05, 2019 04:00 PM CEST
    DATE: September 5, 2019TIME: 7:00am PT, 10:00am ET, 4:00pm CEST PCR (Polymerase Chain Reaction) has gone through a massive evolution since its development in 1983. Besides it...
    JUN 19, 2019 10:00 AM PDT
    JUN 19, 2019 10:00 AM PDT
    DATE: June 19, 2019TIME: 10:00am PDT, 1:00pm EDT As we develop new methods to create more biologically relevant models for research in understanding disease etiology and in...
    JUN 05, 2019 05:00 PM CEST
    C.E. CREDITS
    JUN 05, 2019 05:00 PM CEST
    DATE: June 5, 2019TIME: 8:00am PDT, 11:00am EDT, 5:00pm CEST Eukaryotic cell cultures respond to the most subtle influence. Apart from the risk of contamination, minimal chan...
    NOV 18, 2019 07:00 AM PST
    C.E. CREDITS
    NOV 18, 2019 07:00 AM PST
    DATE: November 18, 2019TIME: 7:00am PST, 11:00am EST, 4:00pm CEWT How often do you pipette in your cell culture lab every day? Usually, we do it so often that we tend stop th...
    MAY 23, 2019 09:00 AM PDT
    C.E. CREDITS
    MAY 23, 2019 09:00 AM PDT
    DATE:  May 23, 2019TIME:   9:00am PDT, 12:00pm EDT Although mesenchymal stem/stromal cells (MSCs) chondrogenic differentiation has been thoroughly investigated...
    Loading Comments...
    Show Resources