Programmed Death Ligand 1 (PD-L1)

Overview

Programmed Death Ligand 1 (PD-L1), also known as CD274 or B7-H1, is a transmembrane glycoprotein and an important immune checkpoint protein encoded by the CD274 gene. It is a member of the B7 family and functions as a co-inhibitory factor of the immune response. PD-L1 interacts with the PD-1 receptor on T cells, leading to reduced T-cell proliferation, decreased cytokine secretion, and induction of apoptosis.

Physiologically, PD-L1 helps maintain immune tolerance and homeostasis, preventing the immune system from attacking healthy cells. However, tumor cells exploit PD-L1 expression to evade immune detection, making it a central mechanism of immune escape in cancers.

PD-L1 is expressed on dendritic cells, B cells, T cells, and tumor cells. Assessing PD-L1 expression in tissues plays a pivotal role in identifying patients eligible for immune checkpoint inhibitor therapies such as anti–PD-1 and anti–PD-L1 treatments.

Symptoms

PD-L1 itself does not cause direct symptoms, but abnormal PD-L1 expression—particularly in cancers—manifests through disease-related clinical signs:

1. General Cancer-Related Symptoms:
   1. Unexplained weight loss
   2. Fatigue and weakness
   3. Persistent fever or night sweats
   4. Loss of appetite
2. Organ-Specific Symptoms:
   1. Lung Cancer: Chronic cough, chest pain, shortness of breath, or hemoptysis.
   2. Bladder Cancer: Hematuria (blood in urine), urinary urgency, or pelvic pain.
   3. Gastric and Esophageal Cancers: Difficulty swallowing, indigestion, abdominal pain, or unintentional weight loss.

The presence of PD-L1 in these tumors is clinically significant as it predicts response to targeted immunotherapies.

Causes

PD-L1 expression can be influenced by both normal physiological processes and pathological mechanisms:

1. Physiological Role:
   1. Maintains immune tolerance by preventing T-cell–mediated destruction of normal cells.
   2. Acts as a brake on excessive immune responses, reducing risk of autoimmunity.
2. Pathological Causes:
   1. Cancer: Tumor cells upregulate PD-L1 to suppress T-cell activity and evade immune detection.
   2. Inflammation: Chronic inflammatory states can alter PD-L1 expression on immune and tissue cells.
   3. Genetic Regulation: CD274 gene activity influences PD-L1 levels, contributing to tumor progression in some cases.

Risk Factors

Risk factors for abnormal PD-L1 expression and associated immune evasion include:

1. Cancer Patients:
   1. Non-small cell lung cancer (NSCLC)
   2. Bladder and urothelial cancers
   3. Gastric and gastroesophageal junction adenocarcinoma
   4. Esophageal squamous cell carcinoma
2. Genetic Alterations: Mutations and regulatory changes in the CD274 gene can promote abnormal PD-L1 expression.
3. Chronic Inflammation: Persistent inflammatory conditions may influence PD-L1 levels, contributing to immune modulation.
4. Patients Undergoing Immunotherapy: Monitoring PD-L1 expression helps predict therapeutic response.

Prevention

While PD-L1 expression itself cannot be entirely prevented, its clinical implications can be managed through proper diagnostic and preventive strategies:

1. Diagnostic Testing and Detection:
   1. PD-L1 expression is evaluated using immunohistochemistry (IHC) on tumor samples.
   2. Tumor Area Positivity (TAP) score combines PD-L1 positive tumor cells and immune cells relative to total tumor area for assessment.
   3. Both circumferential and partial membrane staining are considered positive, while cytoplasmic staining is disregarded.
2. Sample Collection Guidelines:
   1. Bone marrow aspiration: Minimum 2.5 mL.
   2. Blood samples: 6 mL in EDTA (lavender-capped) tubes, divided into 3 mL each.
3. Targeted Therapy:
   1. Immune checkpoint inhibitors (anti–PD-1 and anti–PD-L1 therapies) are cornerstone treatments for cancers with elevated PD-L1 expression.
   2. These therapies restore T-cell activity and improve immune recognition of tumor cells.
4. Clinical Monitoring:
   1. Regular monitoring of PD-L1 expression in cancer patients helps guide treatment and prognosis.
   2. Ensuring timely use of immunotherapies can significantly improve survival outcomes.