PD-1 / PD-L1 immune checkpoint & T-cell activation
How T cells decide to attack. A T cell needs to see the target (TCR-MHC) and get a 'go' signal (CD28). PD-1 and CTLA-4 are 'stop' signals; tumours exploit them. Checkpoint inhibitors remove the stop.
Dendritic cells prime T cells in lymph nodes via peptide-MHC to TCR (signal 1) plus B7 to CD28 (signal 2); CTLA-4 competes for B7 and terminates priming. In the tumour, interferon-gamma from activated T cells induces PD-L1 on tumour and myeloid cells, which engages PD-1 on T cells and inhibits their effector function (adaptive resistance). LAG-3, TIM-3, TIGIT are further exhaustion checkpoints. Anti-CTLA-4 acts at priming; anti-PD-1/PD-L1 in the tumour. Predictors: PD-L1, TMB, MSI, TILs, interferon signatures. Resistance: loss of MHC-I/B2M, JAK1/2, antigen loss, immunosuppressive myeloid cells, TGF-β exclusion.
In one picture
A soldier needs a target in the sights (TCR) and an order to fire (CD28). CTLA-4 is a commander revoking orders during training; PD-1 is a white flag the enemy waves on the battlefield that makes the soldier lower their weapon. Checkpoint inhibitors tear up the white flag.
Diagram
top- Anti-PD-1 (pembrolizumab, nivolumab), anti-PD-L1 (atezolizumab, durvalumab)
- Anti-CTLA-4 (ipilimumab) ± anti-PD-1
- Anti-LAG-3 (relatlimab) + nivolumab
- PD-1×VEGF bispecifics (ivonescimab)
- Vaccines, T-cell engagers, and CAR-T supply signal 1 by other means
This study is why PD-1 inhibitors were developed across cancers rather than in melanoma alone: unexpected activity in lung cancer, historically thought immune-resistant, changed drug development priorities industry-wide. It also introduced PD-L1 immunohistochemistry as a candidate biomarker and pneumonitis as a signature toxicity. Within five years PD-1 blockade was approved in more than ten cancers.
Tumours hide from T cells by displaying PD-L1; blocking that interaction lets the immune system attack. This is the mechanism of pembrolizumab, nivolumab, atezolizumab and their relatives, which now treat more than 20 cancer types.
Every checkpoint inhibitor, from ipilimumab to pembrolizumab, rests on this idea: the immune system can already recognise cancer and just needs its brakes released. It changed the goal of immunotherapy from vaccinating against tumours to unleashing existing T cells.