Pembrolizumab is a PD-1 checkpoint inhibitor used in solid tumours. A patient develops pembrolizumab-induced immune checkpoint myocarditis. The immunological mechanism of this irAE involves:
- A PD-1 blockade disinhibits autoreactive CD8+ T cells that share TCR specificities with both tumour antigens and cardiac myosin/troponin epitopes, causing T cell-mediated cardiomyocyte destruction via molecular mimicry ✓
- B Pembrolizumab-IgG4 antibody complement activation causing direct complement-mediated cardiomyocyte lysis
- C Pembrolizumab causes cytokine release syndrome with IL-6 excess, triggering toxic cardiomyopathy
- D PD-L1 blockade on cardiac macrophages increases M1 polarisation, releasing reactive oxygen species that damage cardiomyocytes
Explanation
Immune checkpoint inhibitor-associated myocarditis (ICIAM) results from disinhibition of autoimmune T cell responses normally suppressed by PD-1/PD-L1 signalling. Evidence from autopsy studies shows massive CD8+ T cell and macrophage infiltration in the myocardium. T cell receptor sequencing has demonstrated that the same T cell clones infiltrate both the tumour and the myocardium, supporting a molecular mimicry model where tumour-reactive T cells cross-react with cardiac antigens (particularly cardiac troponin). ICIAM carries 50% mortality and requires immediate high-dose corticosteroid therapy. It is more common with combination anti-PD-1/anti-CTLA4 therapy (nivolumab + ipilimumab).
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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Written and medically reviewed by the StethoPrep medical team.