MENU

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

C.E. Credits: P.A.C.E. CE Florida CE
Speaker
  • 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
    SEP 10, 2020 9:00 AM PDT
    C.E. CREDITS
    SEP 10, 2020 9:00 AM PDT
    Date: September 10, 2020 Time: 9:00am (PDT), 12:00pm (EDT) Osmolality testing is relevant throughout the entire bioprocessing workflow. As customers look to refine mAb and gene therapy workf...
    DEC 02, 2020 8:00 AM PST
    C.E. CREDITS
    DEC 02, 2020 8:00 AM PST
    DATE: December 2nd, 2020 TIME: 08:00am PDT, 11:00pm EDT Bioreactors and shakers are used to cultivate microorganisms, plant, insect, and mammalian cells in different volumes. Upscaling of pr...
    OCT 29, 2020 6:00 AM PDT
    C.E. CREDITS
    OCT 29, 2020 6:00 AM PDT
    Date: October 29, 2020 Time: 6:00am (PDT), 9:00am (EDT), Chronic inflammation can occur as a result of a combination of genetic predispositions and environmental factors. Epigenetic modifica...
    OCT 08, 2020 7:00 AM PDT
    C.E. CREDITS
    OCT 08, 2020 7:00 AM PDT
    DATE: October 8, 2020 TIME: 7:00am PDT, 10:00am EDT, 4:00pm CEST How often do you pipette in your cell culture lab every day? Usually, we do it so often that we tend stop thinking about ho...
    NOV 16, 2020 8:00 AM PST
    C.E. CREDITS
    NOV 16, 2020 8:00 AM PST
    Date: November 16, 2020 Time: 8:00am (PST), 11:00am (EST) CRISPR screening has become the prime discovery tool in modern biomedical research and drug discovery. At the same time, most screen...
    JUL 22, 2020 10:00 AM PDT
    C.E. CREDITS
    JUL 22, 2020 10:00 AM PDT
    DATE: July 23, 2020 TIME: 10:00 am PDT The SARS-CoV-2 pandemic has taken a toll on many sectors of the medical community. As the pandemic took a grip on the laboratory, the need for diagnost...
    Loading Comments...
    Show Resources