This discovery may increase effectiveness of immunotherapy
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 – in this case, PDL1 – or substances made in a laboratory to improve immune system function.
Mien-Chie Hung, Ph.D., 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.”