What is PD-L1?
PD-L1 (programmed cell death ligand 1) is a key immunoregulatory molecule which, upon interacting with its receptor PD-1, inhibits the CD8 cytotoxic immune response and the resultant antitumor immune response. 1
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 (programmed death protein 1), a negative regulator expressed on T cells 1
- When PD-1 is engaged by its receptors (PD-L1 and PD-L2), T-cell activity is suppressed, which under normal physiological conditions prevents excessive immune responses and autoimmunity 2, 3
- 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
Clinical Significance in Cancer
- PD-L1 expression is an immune evasion mechanism exploited by various malignancies, allowing cancer cells to escape immune surveillance 2, 4
- 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 1
- 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 1
Role in Immunotherapy
- Checkpoint inhibitor antibodies block the PD-1 and PD-L1 interaction, thereby improving the antitumor effects of endogenous T cells 1
- FDA-approved immune checkpoint inhibitors target PD-L1 expressing tumor cells by blocking the PD-L1/PD-1 signaling pathway 1
- PD-L1 expression testing is recommended for all patients with newly diagnosed advanced NSCLC to guide treatment decisions 1
Testing and Measurement
- PD-L1 expression is typically measured using immunohistochemistry (IHC) assays that evaluate membranous immunostaining of tumor cells 1
- Different anti-PD-L1/PD-1 agents require different detection methods and assay conditions 1
- Various scoring systems exist for PD-L1 expression:
- Combined positive score (CPS) is determined by the number of PD-L1–stained cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells evaluated, multiplied by 100 1
- Tumor proportion score (TPS) focuses on the proportion of tumor cells expressing membranous staining 1
- 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 1
Challenges in PD-L1 Testing
- The interpretation of results and scoring systems are different for each antibody and assay 1
- 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 1
- 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
Future Directions
- Alternative or additional biomarkers are being explored to better predict response to immunotherapy, including tumor mutational burden (TMB) 1, 4
- Combination therapies targeting multiple immune checkpoints show promise, such as combining anti-CTLA-4 and anti-PD-1 antibodies 1
- Research into the intrinsic roles of PD-L1 in tumor cells beyond immune evasion may provide new therapeutic targets 3, 5