logo
    Docs
 

Target: CD274


Research on the Target CD274 (PD-L1)

1. Target Summary:

CD274, commonly known as Programmed Death-Ligand 1 (PD-L1), is a protein that plays a crucial role in the immune system's regulation, particularly in the context of cancer. PD-L1 is expressed on the surface of various cells, including tumor cells, and interacts with the PD-1 receptor on T cells, leading to the inhibition of T cell activation and proliferation. This interaction is a key mechanism through which tumors evade immune detection and destruction, making PD-L1 a significant target for cancer immunotherapy.

2. Mechanism:

PD-L1 functions primarily as an immune checkpoint that inhibits T cell responses. When PD-L1 binds to PD-1 on T cells, it activates intracellular signaling pathways that lead to:
  • Inhibition of T cell activation: This interaction reduces the proliferation and cytokine production of T cells, effectively dampening the immune response against tumor cells.
  • Promotion of T cell apoptosis: PD-L1 engagement can lead to programmed cell death in T cells, further diminishing the immune response.
  • Enhancement of regulatory T cell (Treg) function: PD-L1 can promote the differentiation and function of Tregs, which are known to suppress immune responses and maintain immune tolerance (Cha et al., 2019; Sun et al., 2018).
The blockade of the PD-1/PD-L1 pathway using monoclonal antibodies has been shown to restore T cell activity, enhancing anti-tumor immunity and leading to durable responses in various cancers (Yamaguchi et al., 2022).

3. Approved Drugs:

Several PD-L1 inhibitors have been approved for clinical use, including:
  • Atezolizumab (Tecentriq): Approved for various cancers, including non-small cell lung cancer (NSCLC) and bladder cancer.
  • Durvalumab (Imfinzi): Approved for NSCLC and bladder cancer.
  • Avelumab (Bavencio): Approved for Merkel cell carcinoma and bladder cancer. These drugs work by blocking the PD-L1 protein, preventing it from interacting with PD-1, thereby enhancing T cell-mediated immune responses against tumors (Yi et al., 2022).

4. Hypotheses:

  • Hypothesis 1: High levels of PD-L1 expression on tumor cells correlate with poor prognosis and reduced survival rates in cancer patients. This is based on the premise that elevated PD-L1 facilitates immune evasion.
  • Hypothesis 2: Patients with high PD-L1 expression are more likely to respond to PD-1/PD-L1 inhibitors, as these therapies aim to block the inhibitory signals that PD-L1 exerts on T cells.
  • Hypothesis 3: Combination therapies that include PD-L1 inhibitors will yield better clinical outcomes compared to monotherapy, as they may address multiple pathways involved in tumor immune evasion (Hayashi & Nakagawa, 2020).

5. Validation:

Numerous studies have validated PD-L1 as a therapeutic target:
  • Clinical Trials: Trials involving PD-1/PD-L1 inhibitors have shown significant improvements in overall survival and progression-free survival in various cancers, particularly in NSCLC and melanoma (Garon et al., 2015; Cortes et al., 2020).
  • Biomarker Studies: High PD-L1 expression has been associated with better responses to PD-1/PD-L1 inhibitors, supporting its role as a predictive biomarker for treatment efficacy (Brody et al., 2017).

6. Clinical Trials:

Recent clinical trials have focused on:
  • Combination Therapies: Trials investigating the efficacy of PD-L1 inhibitors in combination with chemotherapy, targeted therapies, and other immunotherapies have shown promising results (Yi et al., 2022; Hayashi & Nakagawa, 2020).
  • Ongoing Studies: Numerous ongoing trials are evaluating the safety and efficacy of PD-L1 inhibitors across different cancer types, including gynecologic cancers and hepatocellular carcinoma (Kooshkaki et al., 2020; Lyu et al., 2022).

7. Involved Pathways:

PD-L1 is involved in several key signaling pathways:
  • PD-1/PD-L1 Pathway: This pathway is crucial for immune checkpoint regulation and is a primary target for immunotherapy.
  • TGF-β Signaling: TGF-β can upregulate PD-L1 expression in tumors, contributing to immune evasion.
  • JAK/STAT Pathway: This pathway is involved in the transcriptional regulation of PD-L1 in response to various cytokines (Yamaguchi et al., 2022).

8. Associated Genes:

  • CD274: The gene encoding PD-L1.
  • PDCD1: The gene encoding PD-1, which interacts with PD-L1.
  • JAK1 and JAK2: Genes involved in the signaling pathways that regulate PD-L1 expression.

9. Target Expression:

PD-L1 is expressed on various cell types, including:
  • Tumor Cells: High expression is often observed in many malignancies, including lung, breast, and bladder cancers.
  • Immune Cells: PD-L1 can also be expressed on antigen-presenting cells and Tregs, contributing to immune regulation.

10. Additional Context:

The PD-1/PD-L1 axis is a critical component of the immune response to tumors. Understanding the regulatory mechanisms of PD-L1 expression can help identify patients who are likely to benefit from PD-1/PD-L1 inhibitors and inform the development of combination therapies that enhance treatment efficacy (Zhang et al., 2021).

11. References:

  • Cha, J. H., Chan, L. C., & Li, C. W. (2019). Mechanisms Controlling PD-L1 Expression in Cancer. Molecular Cell, PMID: 31668929.
  • Sun, C., Mezzadra, R., & Schumacher, T. N. (2018). Regulation and Function of the PD-L1 Checkpoint. Immunity, PMID: 29562194.
  • Yi, M., Zheng, X., & Niu, M. (2022). Combination strategies with PD-1/PD-L1 blockade: current advances and future directions. Molecular Cancer, PMID: 35062949.
  • Garon, E. B., Rizvi, N. A., & Hui, R. (2015). Pembrolizumab for the treatment of non-small-cell lung cancer. The New England Journal of Medicine, PMID: 25891174.
  • Brody, R., Zhang, Y., & Ballas, M. (2017). PD-L1 expression in advanced NSCLC: Insights into risk stratification and treatment selection from a systematic literature review. Lung Cancer, PMID: 29191596.
  • Kooshkaki, O., Derakhshani, A., & Safarpour, H. (2020). The Latest Findings of PD-1/PD-L1 Inhibitor Application in Gynecologic Cancers. International Journal of Molecular Sciences, PMID: 32708748.
  • Lyu, N., Yi, J. Z., & Zhao, M. (2022). Immunotherapy in older patients with hepatocellular carcinoma. European Journal of Cancer, PMID: 34954439.
  • Zhang, H., Dai, Z., & Wu, W. (2021). Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer. Journal of Experimental & Clinical Cancer Research, PMID: 34088360.
  • Yamaguchi, H., Hsu, J. M., & Yang, W. H. (2022). Mechanisms regulating PD-L1 expression in cancers and associated opportunities for novel small-molecule therapeutics. Nature Reviews Clinical Oncology, PMID: 35132224.