Pembrolizumab's mechanism of action in cancer immunotherapy involves blocking the PD-1/PD-L1 checkpoint. The reason PD-1 blockade is more effective than PD-L1 blockade in some tumors relates to the fact that PD-1 also interacts with:

• A CD28 receptor, acting as a co-stimulatory agonist that paradoxically suppresses cytotoxic T-cell expansion
• B LAG-3 through cis-interactions on T-cells creating composite exhaustion signals not blocked by PD-L1 antibodies
• C PD-L2 (B7-DC), which is expressed on tumor cells and professional APCs and can also suppress T-cell responses independently of PD-L1 ✓
• D CTLA-4 ligands (CD80/CD86) through receptor cross-talk depleting regulatory T-cell populations

Explanation

PD-1 (programmed death-1) has two known ligands: PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273). Anti-PD-1 antibodies (pembrolizumab, nivolumab) block PD-1's interaction with both PD-L1 and PD-L2 simultaneously. Anti-PD-L1 antibodies (atezolizumab, durvalumab) block only the PD-L1 pathway. PD-L2 is expressed on dendritic cells and some tumor cells; its suppressive signaling through PD-1 would be missed by anti-PD-L1 therapy. This dual ligand blockade may confer a broader immunostimulatory advantage of anti-PD-1 agents in tumors expressing PD-L2. LAG-3 is a separate inhibitory receptor (not a PD-1 ligand) targeted by relatlimab in combination.

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

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Written and medically reviewed by the StethoPrep medical team.