PD-1 receptor

PD-1 is a transmembrane protein belonging to the CD28/CTLA-4 immunoglobulin superfamily. Upon chronic antigen exposure (e.g., in tumors or chronic infections), T cells upregulate PD-1. Engagement of PD-1 by its ligands PD-L1 (B7-H1) or PD-L2 (B7-DC) recruits SHP-2 phosphatase, which dephosphorylates key signaling molecules downstream of the T-cell receptor (TCR) and CD28, reducing T-cell proliferation, cytokine production, and cytotoxic function. This mechanism normally prevents autoimmunity and limits tissue damage during chronic inflammation (T-cell exhaustion), but many tumors upregulate PD-L1 to inhibit anti-tumor T-cell responses, enabling immune escape.

Clinically, PD-1/PD-L1 inhibitors (checkpoint inhibitors) have revolutionized oncology. Examples include pembrolizumab and nivolumab (anti-PD-1 antibodies) and atezolizumab, durvalumab, avelumab (anti-PD-L1 antibodies). These drugs block the inhibitory signal, "releasing the brakes" on T cells to enhance anti-tumor immunity. They are used in melanoma, non-small cell lung cancer, renal cell carcinoma, Hodgkin lymphoma, and other malignancies, often with PD-L1 expression as a biomarker for response.

Key adverse effects relate to immune hyperactivation: immune-related adverse events (irAEs) including pneumonitis, colitis, hepatitis, hypophysitis, thyroiditis, and dermatitis, due to loss of peripheral tolerance. Management typically involves corticosteroids and discontinuation of therapy in severe cases.

PD-1 deficiency or dysregulation is also linked to autoimmune phenomena in some genetic models. Distinguishing PD-1/PD-L1 from CTLA-4 (another checkpoint, targeted by ipilimumab, acting earlier in T-cell priming in lymph nodes rather than in the periphery/tumor microenvironment) is a common board distinction.