Quantifying PD-L1 Expression to Monitor Immune Checkpoint Therapy: Opportunities and Challenges

SIMPLE SUMMARY: Malignant cells hijack the regulatory roles of immune checkpoint proteins for immune evasion and survival. Therapeutics blocking those proteins can restore the balance of the immune system and lead to durable responses in cancer patients. Although a subset of patients derive benefit, there are few non-invasive technologies to guide and monitor those therapies to improve success rates. This is a review of the advancements in non-invasive methods for quantification of immune checkpoint protein programmed death ligand 1 expression, a biomarker detected by immunohistochemistry and widely used for guiding immune checkpoint therapy. ABSTRACT: Therapeutics targeting programmed death ligand 1 (PD-L1) protein and its receptor PD-1 are now dominant players in restoring anti-tumor immune responses. PD-L1 detection by immunohistochemistry (IHC) is emerging as a reproducible biomarker for guiding patient stratification for those therapies in some cancers. However, PD-L1 expression in the tumor microenvironment is highly complex. It is upregulated by aberrant genetic alterations, and is highly regulated at the transcriptional, posttranscriptional, and protein levels. Thus, PD-L1 IHC is inadequate to fully understand the relevance of PD-L1 levels in the whole body and their dynamics to improve therapeutic outcomes. Imaging technologies could potentially assist in meeting that need. Early clinical investigations show promising results in quantifying PD-L1 expression in the whole body by positron emission tomography (PET). Within this context, this review summarizes advancements in regulation of PD-L1 expression and imaging agents, and in PD-L1 PET for drug development, and discusses opportunities and challenges presented by these innovations for guiding immune checkpoint therapy (ICT).