{"entity":{"id":"pd1-checkpoint","kind":"pathway","name":"PD-1 / PD-L1 immune checkpoint & T-cell activation","aka":[],"tldr":"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.","summary":"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.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Immune_checkpoint","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Immune_checkpoint"},{"label":"Green et al., Blood 2010: selective 9p24.1 amplification and PD-1 ligand induction through JAK2 in Hodgkin lymphoma and mediastinal large B-cell lymphoma","url":"https://doi.org/10.1182/blood-2010-05-282780"},{"label":"Roemer et al., J Clin Oncol 2016: PD-L1 and PD-L2 genetic alterations in 108 classical Hodgkin lymphomas","url":"https://doi.org/10.1200/JCO.2016.66.4482"}],"tags":[],"related":[],"cancers":["melanoma","nsclc","tnbc","rcc","urothelial","non-hodgkin-lymphoma","hodgkin-lymphoma","primary-mediastinal-b-cell-lymphoma"],"sections":[],"technologies":["checkpoint-inhibitor","t-cell-engager","neoantigen-mrna-vaccine"],"targets":["pd1","pdl1","ctla4","lag3","tigit","cd3","cd80","cd28","b7h4"],"drugs":["pembrolizumab","nivolumab","ipilimumab","atezolizumab","durvalumab","relatlimab-nivolumab","ivonescimab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Lymphoma: Hodgkin lymphoma and primary mediastinal B-cell lymphoma are the two diseases in which the checkpoint is switched on by a copy-number event rather than by the microenvironment. The 9p24.1 amplicon carries CD274, PDCD1LG2 and JAK2, so the ligands rise by gene dose and by transcription at once (Green 2010), and 97% of 108 classical Hodgkin lymphomas carried concordant alterations of the two ligand loci (Roemer 2016)."],"analogy":"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.","nodes":[{"id":"dc","label":"Dendritic cell (antigen + B7)","x":20,"y":8},{"id":"tcr","label":"TCR-peptide/MHC","x":20,"y":28},{"id":"cd28","label":"CD28-B7 (go)","x":50,"y":28},{"id":"ctla4","label":"CTLA-4 (stop)","x":80,"y":28,"targetId":"ctla4"},{"id":"tcell","label":"Activated CD8 T cell","x":50,"y":50},{"id":"ifn","label":"IFN-γ","x":80,"y":62},{"id":"pdl1","label":"PD-L1 on tumour","x":80,"y":80,"targetId":"pdl1"},{"id":"pd1","label":"PD-1 on T cell","x":50,"y":70,"targetId":"pd1"},{"id":"lag3","label":"LAG-3 / TIGIT","x":20,"y":70,"targetId":"lag3"},{"id":"kill","label":"Tumour cell killing","x":50,"y":95}],"edges":[{"from":"dc","to":"tcr","type":"activates"},{"from":"dc","to":"cd28","type":"activates"},{"from":"tcr","to":"tcell","type":"activates"},{"from":"cd28","to":"tcell","type":"activates"},{"from":"ctla4","to":"cd28","type":"inhibits"},{"from":"tcell","to":"ifn","type":"activates"},{"from":"ifn","to":"pdl1","type":"activates"},{"from":"pdl1","to":"pd1","type":"activates"},{"from":"pd1","to":"tcell","type":"inhibits"},{"from":"lag3","to":"tcell","type":"inhibits"},{"from":"tcell","to":"kill","type":"activates"}],"interventions":["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"]},"route":"/pathways/pd1-checkpoint/","neighbours":{"cancer":[{"id":"advanced-melanoma","kind":"cancer","name":"Advanced melanoma (unresectable stage III and stage 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