A patient with metastatic melanoma develops immune checkpoint inhibitor-related pneumonitis while on pembrolizumab. Management with steroids is initiated. Which mechanism specifically explains why pembrolizumab causes autoimmune adverse effects?
- A Pembrolizumab's Fc region activates complement and macrophages in off-target tissues via ADCP
- B PD-1 blockade removes the brake on previously tolerized autoreactive T cells in peripheral tissues, allowing them to attack self-antigens in affected organs ✓
- C PD-1 blockade in regulatory T cells (Tregs) paradoxically increases Treg function, causing uncontrolled immunosuppression and opportunistic infections
- D Pembrolizumab induces upregulation of CTLA-4 on activated T cells, creating a dysregulated T-cell co-stimulatory environment
Explanation
PD-1 (programmed death-1) is expressed on activated effector T cells, exhausted T cells, and Tregs. Its natural ligands, PD-L1 and PD-L2, are expressed on tumour cells, antigen-presenting cells, and peripheral tissue cells, where they deliver an inhibitory signal to T cells — maintaining peripheral tolerance by suppressing autoreactive T cells that escaped central thymic deletion. Pembrolizumab (anti-PD-1 humanized IgG4 antibody) blocks this inhibitory signal, reinvigorating exhausted tumour-infiltrating T cells to attack cancer. However, the same mechanism also removes the peripheral tolerance checkpoint from autoreactive T cells throughout the body — allowing them to infiltrate and damage normal tissues including lung (pneumonitis), colon (colitis), pituitary (hypophysitis), thyroid (thyroiditis), liver (hepatitis), and skin (dermatitis). The grade and organ pattern of immune-related adverse events (irAEs) require prompt corticosteroid therapy and, in severe cases, permanent discontinuation of the checkpoint inhibitor.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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Written and medically reviewed by the StethoPrep medical team.