Pembrolizumab exerts its anti-tumour effect by blocking PD-1 on T cells. The downstream signalling consequence of PD-1 activation that pembrolizumab reverses is:
- A Activation of PI3K-AKT pathway promoting regulatory T cell (Treg) differentiation and suppression
- B Direct apoptosis induction in cytotoxic T lymphocytes via Fas-FasL pathway activation
- C SHP-1/SHP-2 phosphatase recruitment dephosphorylating ZAP-70 and CD28 signalling components, reducing T-cell activation ✓
- D CTLA-4 upregulation on T cells creating redundant immune checkpoint activation
Explanation
When PD-L1 (on tumour cells or APCs) binds PD-1 on T cells, the cytoplasmic tail of PD-1 (ITSM and ITIM motifs) recruits SHP-1 and SHP-2 protein tyrosine phosphatases. These phosphatases dephosphorylate key signalling molecules including ZAP-70 (TCR proximal kinase) and the CD28 co-stimulatory pathway components, directly dampening TCR signalling strength and reducing cytokine production and cytotoxic function ('exhaustion'). Pembrolizumab and nivolumab blocking PD-1 prevent this phosphatase recruitment, restoring T-cell effector function. PD-1 also suppresses PI3K-AKT via PTEN upregulation, but SHP recruitment is the primary proximal mechanism. PD-1 does not directly activate Fas or upregulate CTLA-4.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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Written and medically reviewed by the StethoPrep medical team.