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.