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 Atezolizumab

Learn more about Cemiplimab

Learn more about Durvalumab and Tremelimumab

Learn more about Nivolumab and Ipilimumab

Learn more about Pembrolizumab

References

  1. 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
  2. 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
  3. Han Y, Liu D, Li L. PD-1/PD-L1 pathway: current researches in cancer. Am J Cancer Res. 2020;10(3):727-742.
  4. National Comprehensive Cancer Network. NCCN guidelines version 4.2024: Non-Small Cell Lung Cancer. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
  5. Merck. Keytruda (Pembrolizumab) [Package Insert].; 2024.
  6. Bristol Myers Squibb. Opdivo (Nivolumab) [Package Insert].; 2024.
  7. Bristol Myers Squibb. Yervoy (Ipilimumab) [Package Insert].; 2023.
  8. Bristol Myers Squibb. Libtayo (Cemiplimab-Rwlc) [Package Insert].; 2024.