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Two cellular pathways have been shown to play a role in regulating the immune-system protein PDL1, a finding that could lead to increased efficiency of immunotherapy to fight breast and other cancers. Immunotherapy is a type of cancer treatment designed to boost the body¡¯s natural defenses to fight cancer. It uses substances either made by the body ¨C in this case, PDL1 ¨C or substances made in a laboratory to improve immune system function.

, chair of Molecular & Cellular Oncology, led a team that tied ubiquitination and glycosylation pathways to the stringent regulation of PDL1. The scientists found that glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity.

¡°We knew that extracellular interaction between programmed death ligand-1 or PDL1, and programmed cell death protein-1 also called PD-1, leads to tumor-associated immune escape,¡± said Hung. ¡°Our team found that a glycogen synthase kinase called GSK3 beta interacts with PDL1 and induces phosphorylation-dependent proteasome degradation of PDL1.¡±

The finding is important given that promising clinical outcomes in trials testing antibody blockade of the PD1-PDL1 pathway in melanoma, lung cancer and kidney cancer have resulted in new treatment options for a broad spectrum of malignant cancers.

The study results were published in the Aug. 30, 2016 issue of Nature Communications.

Hung¡¯s team focused on PDL1 for its unique ability to stave off the immune system¡¯s cancer-busting abilities.

¡°Unlike CTLA-4 or PD1, which are primarily expressed in immune cells, PDL1 is expressed in cancer cells and macrophages and plays a major role in inhibiting immune surveillance,¡± said Hung. ¡°In this study, we dissected the mechanisms by which cancer cells initiate T-cell immunosuppression by inducing PDL1 stabilization.¡±

The team demonstrated a ¡°novel¡± interchange between glycosylation and phosphorylation regulating ubiquitination and degradation of PDL1, a regulatory event critical for basal-like breast cancer cells (BLBC) that escape immune surveillance via PDL1-PD1 interaction.

¡°Importantly, inhibition of epithelial growth factor-mediated PDL1 stabilization enhances a therapeutic efficacy of PD1 blockade to promote tumor-infiltrating cytotoxic T-cell immune response,¡± said Hung. ¡°Thus, targeting PDL1 stabilization provides a new strategy to combat BLBC-mediated immunosuppression and may potentially apply to other cancer types.¡±