PD-L1 Expression and Immunotherapy

Molecular and Functional Characteristics

• PD-L1 is a co-regulatory molecule that can be expressed on tumor cells and inhibit T-cell–mediated cell death by binding to PD-1, a negative regulator expressed on T cells 3, 4
• In various tumors, including lung cancer, PD-L1 is often overexpressed on tumor cells and plays an important role in modulating the immune response to both the tumor and host cells 1, 2

Clinical Significance in Cancer

• PD-L1 expression is frequently observed in certain cancer subtypes, such as the intestinal subtype of gastric cancer, and is often associated with MSI-H and Epstein-Barr virus positivity in gastric tumors 5
• The prognostic significance of PD-L1 in cancer remains unclear, with some studies suggesting a favorable association with survival outcomes while others show an unfavorable or no relationship 5

Role in Immunotherapy

• Checkpoint inhibitor antibodies block the PD-1 and PD-L1 interaction, thereby improving the antitumor effects of endogenous T cells 3, 4
• FDA-approved immune checkpoint inhibitors target PD-L1 expressing tumor cells by blocking the PD-L1/PD-1 signaling pathway 1, 2
• PD-L1 expression testing is recommended for all patients with newly diagnosed advanced NSCLC to guide treatment decisions 6

Testing and Measurement

• PD-L1 expression is typically measured using immunohistochemistry (IHC) assays that evaluate membranous immunostaining of tumor cells 5, 3
• Various scoring systems exist for PD-L1 expression, including Combined Positive Score (CPS) and Tumor Proportion Score (TPS) 5, 3, 4
• The FDA-approved IHC assay for PD-L1 utilizes a cutoff of 50% tumor proportion score for first-line and 1% tumor proportion score for second-line therapy with pembrolizumab 3, 4

Challenges in PD-L1 Testing

• PD-L1 is not a perfect biomarker; less than half of biomarker-selected patients benefit from treatment and some responses may be encountered in 'biomarker-negative' cohorts 7, 6
• There is a need to develop a novel and universal biomarker to assess PD-L1 expression, rather than using individual markers and/or individual scoring systems 1, 2

Future Directions

• Alternative or additional biomarkers are being explored to better predict response to immunotherapy, including tumor mutational burden (TMB) 6
• Combination therapies targeting multiple immune checkpoints show promise, such as combining anti-CTLA-4 and anti-PD-1 antibodies 7