PD-L1
Programmed death ligand 1 (PD-L1)
PD-L1 Biology
Programmed Cell Death Protein 1 (PD-1) is an immunosuppressive checkpoint expressed in immune cells, including in tumor-specific activated T cells, under conditions of chronic antigen exposure.1,2 Programmed Death Ligand 1 (PD-L1) is a PD-1 ligand expressed by various immune cells, including activated T cells, B cells, and epithelial cells under inflammatory conditions.3 Under normal circumstances, this system of proteins modulates the innate tumor response.3 The advent of immune checkpoint inhibitors (ICI) that target the PD-1/PD-L1 pathway in patients with advanced NSCLC represents a significant improvement over traditional chemotherapy, especially in patients with high PD-L1 expression. However, challenges remain; these include the occurrence of hyper-progressive disease in some patients treated with these inhibitors, which points to a need for better patient selection and understanding of resistance mechanisms.1 PD-L1 is expressed in tumor cells, tumor-infiltrating cells, and antigen-presenting cells in many cancers, including NSCLC.1,2 Higher levels of PD-L1 expression are associated with increased tumor proliferation, aggressiveness, and poorer survival.2 The expression of PD-L1 by tumor cells suppresses T-cell function, enabling tumors to evade immune detection.1,2
PD-L1 Testing
PD-L1 levels have shown promise as prognostic biomarkers and therapeutic targets for immunotherapies that block the PD-1/PD-L1 pathway, but their clinical significance varies across cancer types.1 The NCCN recommends testing for multiple molecular markers in all patients with metastatic NSCLC, including PD-L1 status. Still, they note that oncogenic drivers should take precedence over treatment with immune checkpoint inhibitors.4 An FDA-approved immunohistochemistry (IHC) test should be used to determine the proportion of tumor cells expressing membranous staining for PD-L1; clinicians should avoid using multiple IHC assays.4
Treatment
Multiple FDA-approved ICI options are available for treating advanced NSCLC in patients with high PD-L1 expression (≥50%).5–8 ICIs are approved in combination with or without traditional chemotherapy, with ICI-only options including pembrolizumab, nivolumab with ipilimumab, and cemilumab.5–8 Three of these options are monoclonal antibodies that attach to PD-1 and interrupt the PD-L1 interaction: pembrolizumab, nivolumab, and cemilumab. Disrupting this process obviates tumor cells’ ability to utilize this system to avoid immune system attacks.5,6,8 Ipilimumab works via the complementary mechanism of attaching to and disrupting CTLA-4, which is a down-regulator of T cell activation; blocking it increases T cell and tumor lysis activity.7
Learn more about Durvalumab and Tremelimumab
Learn more about Nivolumab and Ipilimumab
Learn more about Pembrolizumab
References
- Tang Q, Chen Y, Li X, et al. The role of PD-1/PD-L1 and application of immune-checkpoint inhibitors in human cancers. Front Immunol. 2022;13:964442. doi:10.3389/fimmu.2022.964442
- Pawelczyk K, Piotrowska A, Ciesielska U, et al. Role of PD-L1 Expression in Non-Small Cell Lung Cancer and Their Prognostic Significance according to Clinicopathological Factors and Diagnostic Markers. IJMS. 2019;20(4):824. doi:10.3390/ijms20040824
- Han Y, Liu D, Li L. PD-1/PD-L1 pathway: current researches in cancer. Am J Cancer Res. 2020;10(3):727-742.
- National Comprehensive Cancer Network. NCCN guidelines version 4.2024: Non-Small Cell Lung Cancer. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
- Merck. Keytruda (Pembrolizumab) [Package Insert].; 2024.
- Bristol Myers Squibb. Opdivo (Nivolumab) [Package Insert].; 2024.
- Bristol Myers Squibb. Yervoy (Ipilimumab) [Package Insert].; 2023.
- Bristol Myers Squibb. Libtayo (Cemiplimab-Rwlc) [Package Insert].; 2024.