PD-L1 testing, fit for routine evaluation? From a pathologist's point of view

Area of Science:

• Oncology
• Immunology
• Biomarker Discovery

Background:

• High somatic mutation rates in tumors can lead to immune evasion via programmed death-receptor 1/programmed death-ligand 1 (PD-1/PD-L1) upregulation.
• Immune checkpoint inhibitors (ICIs) show promise in non-small cell lung cancer (NSCLC) treatment, potentially for first or second-line therapy.
• Current PD-L1 expression testing via immunohistochemistry (IHC) on tumor cells has limitations as a predictive biomarker.

Approach:

• This review analyzes 30 journal articles and 3 reviews from the past 3 years on PD-L1 as a predictive biomarker in NSCLC.
• The review discusses the variability and influencing factors of PD-L1 IHC testing, including pre-analytical variables, antibody clones, specimen types, and interobserver variability.
• The inducible nature of PD-L1 expression and its dependence on immunological status are considered.

Key Points:

• PD-L1 IHC expression on tumor cells is not always reliably associated with better patient outcomes in NSCLC.
• Factors such as pre-analytical variables, staining platforms, specimen types, and observer variability significantly impact PD-L1 IHC results.
• Understanding PD-L1 expression requires acknowledging it as an inducible factor with variable levels dependent on the patient's immunological status.

Conclusions:

• The predictive value of PD-L1 as a biomarker for ICI therapy in NSCLC is questionable.
• Alternative predictive biomarkers, including high tumor mutational burden, mRNA expression, neo-antigens, and tumor antigen-specific T-cell diversity, warrant future evaluation.
• The timing of PD-L1 testing in relation to initiating immune checkpoint therapy requires careful consideration.