Th169 - Understanding PD-L1 Regulation and Secretion: Insights to Improve Immune Checkpoint Inhibitor Therapies

Abstract Text: PD-L1 Immune Checkpoint Inhibitors (ICI) have revolutionized cancer therapies, but less than 40% of patients benefit from them. Understanding the cell regulation of PD-L1 is key to explain the low response rates and improve therapy.
PD-L1 is often expressed at the surface of tumor cells, particularly in the presence of IFNγ, leading to immune response inhibition. However, basal expression can vary from cell to cell. Importantly, PD-L1 can be released into circulation as a soluble protein or in extracellular vesicles (EV), both able to bind the PD-1 receptor. Despite their role in immune evasion, these soluble forms are often not considered in patient selection.
Here, we compared the cell biology of PD-L1 in cancer cell transfectants with several bladder and metastatic melanoma cancer cell lines expressing endogenous PD-L1, where PD-L1 expression is typically much lower.
A detailed analysis reveals that PD-L1 intracellular trafficking and secretion routes vary markedly between cancer cells from the same tissue, as does the intensity of IFNγ-induced PD-L1 upregulation. Notably, cells with high basal PD-L1 expression showed increased secretion of this molecule in EV. Furthermore, metalloprotease blockade can enhance PD-L1 secretion in EV, suggesting a connection between these two cellular pathways. Since secreted PD-L1 affects PD1 function, especially when multimerized in EV, variability in release routes may explain differences in ICI therapy outcomes.
The intrinsic background of the cell, thus, affects multiple aspects of cellular PD-L1 expression. So, personalizing PD-L1 detection could be important to identify patients who would benefit from PD-L1 directed therapies.