Programmed death ligand-1 expression in gastrointestinal cancer: Clinical significance and future challenges

Cancer immunotherapy has caused a paradigm shift from conventional therapies that directly target cancer cells to innovative therapies that utilize the host immune system. In particular, programmed cell death-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors have achieved an impressive breakthrough and been approved for clinical use in several types of cancer including gastrointestinal (GI) cancer. To identify and develop predictive biomarkers for PD-1 inhibitors is of great concern in clinical practice. Although PD-L1 expression is considered a logical biomarker as PD-L1 is a substantial target of the immune checkpoint inhibitors, its clinical significance in GI cancer remains unclear. In this review, we summarize the current evidence for PD-L1 expression as a prognostic and predictive biomarker for PD-1/PD-L1 inhibitors in GI cancer from recent publications, and emerging evidence from recent key clinical trials on the efficacy of PD-1/PD-L1 inhibitors. Challenging clinical issues for PD-L1 assessment are then discussed from the viewpoint of the methodology for PD-L1 evaluation including the differences in PD-L1 detection assays and evaluation criteria for PD-L1 positivity. Moreover, we highlight the biological features of PD-L1 expression in terms of tumor spatial and temporal heterogeneity, which suggests important implications for biomarker analysis. Finally, we describe future perspectives using liquid biopsy for better assessment of PD-L1 status. This new information should improve our understanding of the clinical significance of PD-L1 in GI cancer, leading to optimal patient selection and treatment strategy for the clinical use of PD-1/PD-L1 inhibitors in patients with GI cancer.