What is the role of Programmed Death-Ligand 1 (PD-L1)?

From the Guidelines

PD-L1 expression is not a reliable biomarker for predicting treatment response to immunotherapy in patients with advanced renal cell carcinoma (RCC) and should not be routinely tested for, as the benefit of treatment with checkpoint inhibitors is observed across all tumor PD-L1 expression levels. The role of PD-L1 expression in predicting response to immunotherapy is complex and varies by cancer type. In the context of RCC, several studies have investigated the relationship between PD-L1 expression and treatment outcomes with checkpoint inhibitors. For example, the CheckMate 025 study found that PD-L1 expression was prognostic of poor outcome but not predictive of an overall survival effect with nivolumab monotherapy 1. Similarly, the CheckMate 214 study found that the benefit of nivolumab plus ipilimumab was observed across all tumor PD-L1 expression levels, although the benefit was enhanced in the population with ≥1% PD-L1 expression 1.

Some key points to consider when evaluating the role of PD-L1 in immunotherapy include:

• The predictive value of PD-L1 expression varies by cancer type and treatment regimen
• PD-L1 expression is not a reliable biomarker for predicting treatment response in RCC
• Treatment with checkpoint inhibitors can be beneficial regardless of PD-L1 expression level
• The use of PD-L1 inhibitors, such as atezolizumab, has been shown to improve outcomes in certain cancer types, including triple-negative breast cancer with PD-L1 expression in ≥1% tumor-infiltrating immune cells 1

In terms of treatment regimens, checkpoint inhibitors are typically administered intravenously every 2-6 weeks, depending on the specific drug, and treatment continues until disease progression or unacceptable toxicity. Side effects can include immune-related adverse events, such as inflammation in various organs. Overall, the decision to use immunotherapy should be based on individual patient characteristics and tumor type, rather than relying solely on PD-L1 expression levels.

From the FDA Drug Label

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action Expression of programmed cell death ligand-1 (PD-L1) can be induced by inflammatory signals (e.g., IFN-gamma) and can be expressed on both tumor cells and tumor-associated immune cells in the tumor microenvironment. PD-L1 blocks T-cell function and activation through interaction with PD-1 and CD80 (B7. 1). By binding to its receptors, PD-L1 reduces cytotoxic T-cell activity, proliferation, and cytokine production. Durvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80 (B7. 1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, without inducing antibody dependent cell-mediated cytotoxicity (ADCC). PD-L1 blockade with durvalumab led to increased T-cell activation in vitro and decreased tumor size in co-engrafted human tumor and immune cell xenograft mouse models.

Programmed Death-Ligand 1 (PD-L1) is a protein that can be expressed on tumor cells and tumor-associated immune cells, and it plays a role in blocking T-cell function and activation.

• PD-L1 Mechanism: PD-L1 interacts with PD-1 and CD80 (B7.1) receptors, reducing cytotoxic T-cell activity, proliferation, and cytokine production.
• Durvalumab and Avelumab: Both durvalumab and avelumab are monoclonal antibodies that bind to PD-L1, blocking its interaction with PD-1 and CD80 (B7.1) and releasing the inhibition of immune responses.
• Key Points:
  • PD-L1 expression can be induced by inflammatory signals.
  • PD-L1 blocks T-cell function and activation.
  • Durvalumab and avelumab bind to PD-L1, blocking its interaction with PD-1 and CD80 (B7.1).
  • Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses. 2 3

From the Research

Programmed Death-Ligand 1 (PD-L1) Overview

• PD-L1 is the principal ligand of programmed death 1 (PD-1), a coinhibitory receptor that can be constitutively expressed or induced in myeloid, lymphoid, normal epithelial cells, and in cancer 4.
• The PD-1/PD-L1 interaction is essential in the development of immune tolerance, preventing excessive immune cell activity that can lead to tissue destruction and autoimmunity 4.

Role of PD-L1 in Cancer

• PD-L1 expression is an immune evasion mechanism exploited by various malignancies and is generally associated with poorer prognosis 4.
• PD-L1 expression is also suggested as a predictive biomarker of response to anti-PD-1/PD-L1 therapies, although contradictory evidence exists as to its role across histotypes 4.
• Abnormally high PD-L1 expression on tumor cells and antigen-presenting cells in the tumor microenvironment mediates tumor immune escape 5.

PD-L1 Signaling and Cancer Immunotherapy

• The PD-1/PD-L1 signaling pathway plays a central role in regulating T cell exhaustion, and blocking this pathway can reduce the inhibitory effect of PD-1 on T cells, promoting anti-tumor activity 5, 6.
• Cancer immunotherapy using PD-1/PD-L1 immune checkpoint blockade has shown promise in treating various types of cancer, including metastatic lung cancer, melanoma, and others 4, 5, 7.
• PD-L1 signals in cancer cells can also control tumor growth and survival pathways, stemness, immune effects, DNA damage responses, and gene expression regulation, independent of PD-1 8.

Challenges and Future Directions

• Despite the effectiveness of PD-1/PD-L1 immunotherapy, there are shortcomings due to the complexity of the tumor microenvironment, and further research is needed to optimize anticancer potential 6, 7.
• The relationship between the PD-1/PD-L1 pathway, regulatory T cells, and T helper 17 cells is not fully clarified, and more studies are needed to understand their interplay in tumor immunity 6.