Pembrolizumab is a PD-1 checkpoint inhibitor. Its immune-related adverse effects (irAEs) share a common pathophysiology. The mechanism of irAEs is:
- A Direct cytotoxicity of pembrolizumab to normal tissues via complement activation
- B Pembrolizumab-induced cytokine release syndrome (CRS) with systemic macrophage activation
- C Loss of PD-1-mediated peripheral immune tolerance, allowing autoreactive T cells to attack normal tissues expressing PD-L1 or autoantigens — mimicking autoimmune disease in any organ ✓
- D Antibody-dependent cellular cytotoxicity (ADCC) by pembrolizumab against PD-1-expressing regulatory T cells in peripheral blood
Explanation
PD-1 (programmed death-1) on T cells, when engaged by its ligands PD-L1 or PD-L2 on tumour cells and normal tissues, normally delivers an inhibitory signal that dampens T cell activity — a key peripheral tolerance mechanism preventing autoimmunity. Pembrolizumab blocks PD-1, releasing autoreactive and tumour-specific T cells from this brake. In normal tissues that express PD-L1 (thyroid, gut, pituitary, skin, lung, joints), this can produce immune-mediated (autoimmune-like) inflammation — irAEs — including thyroiditis, colitis, pneumonitis, dermatitis, and hypophysitis. IrAEs are managed with corticosteroids. They are not CRS or ADCC-mediated.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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Written and medically reviewed by the StethoPrep medical team.