PD-L1

PD-L1 is a transmembrane protein expressed on antigen-presenting cells, various tissues, and notably many tumor cells. It binds PD-1 (Programmed Death-1) receptors on activated T cells, triggering downstream inhibitory signaling that reduces T-cell proliferation, cytokine production, and cytotoxic activity. This PD-1/PD-L1 axis normally functions as an immune checkpoint to prevent autoimmunity and limit collateral tissue damage during chronic immune responses (e.g., peripheral tolerance, prevention of excessive inflammation).

In oncology, tumors exploit this pathway by upregulating PD-L1 expression, effectively cloaking themselves from T-cell-mediated destruction—a mechanism termed 'adaptive immune resistance.' This has become a major target for cancer immunotherapy: checkpoint inhibitors like anti-PD-1 antibodies (nivolumab, pembrolizumab) and anti-PD-L1 antibodies (atezolizumab, durvalumab, avelumab) block this interaction, restoring T-cell-mediated antitumor immunity.

Clinically, PD-L1 expression (measured via immunohistochemistry, often reported as Tumor Proportion Score or Combined Positive Score) is used as a predictive biomarker in cancers such as non-small cell lung cancer, melanoma, urothelial carcinoma, and others to help select patients likely to benefit from checkpoint inhibitor therapy, though response can occur even with low PD-L1 expression.

Important board-relevant associations: immune-related adverse events (irAEs) from checkpoint inhibitor therapy—colitis, pneumonitis, hepatitis, endocrinopathies (hypophysitis, thyroiditis, adrenal insufficiency), and dermatitis—result from the loss of peripheral tolerance when this checkpoint is blocked. Mechanistically distinguish PD-1/PD-L1 inhibitors from CTLA-4 inhibitors (ipilimumab), which act earlier in T-cell activation by blocking CD28-B7 costimulation in lymph nodes.