Checkpoint inhibitors like pembrolizumab act on the immune system rather than directly on tumor cells. Its target, PD-1, when ligated by PD-L1 expressed on tumors, causes:

• A T-cell exhaustion/inactivation by phosphatase-mediated dephosphorylation of TCR signaling intermediates, allowing tumor immune evasion ✓
• B Activation of cytotoxic T-cells by providing co-stimulatory signal 2
• C NK cell degranulation leading to tumor cell apoptosis
• D Dendritic cell maturation and increased antigen presentation to T cells

Explanation

PD-1 (programmed death-1) is an inhibitory receptor on T-cells. When tumor cells express PD-L1, it engages T-cell PD-1, recruiting SHP-2 phosphatase which dephosphorylates and inactivates downstream TCR/CD28 signaling cascades, leading to T-cell exhaustion and failure to kill tumor cells. Pembrolizumab/nivolumab block PD-1, preventing this inhibitory signaling, restoring T-cell cytotoxic activity. Atezolizumab/durvalumab target PD-L1. Ipilimumab targets CTLA-4, another checkpoint. Immune-related adverse events (colitis, pneumonitis) result from off-target immune activation.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.