{"entity":{"id":"paper-iwai-pdl1-tumour-escape-pnas-2002","kind":"paper","name":"Iwai and Honjo: tumours use PD-L1 to escape T cells, and blocking it restores attack","aka":[],"tldr":"A decade after Honjo's group cloned PD-1 (1992), this study showed that tumour cells expressing PD-L1 resist killing by cytotoxic T cells in mice, and that anti-PD-L1 antibody or PD-1 deficiency restores tumour rejection, the foundation of PD-1/PD-L1 therapy.","summary":"Tasuku Honjo's group discovered PD-1 in 1992 (Ishida et al., EMBO J) as a gene induced during programmed cell death in T-cell lines, and later showed PD-1-deficient mice develop autoimmunity, identifying it as an inhibitory receptor. PD-L1 (B7-H1) was identified as its ligand by Freeman, Honjo and colleagues in 2000.\n\nIn this paper, P815 mastocytoma cells transfected with PD-L1 were less susceptible to lysis by cytotoxic T lymphocytes in vitro and grew more aggressively in vivo; anti-PD-L1 antibody reversed this. Myeloma cells naturally expressing PD-L1 grew in wild-type mice but were rejected in PD-1-deficient mice. In parallel, Dong and Chen (Nature Medicine 2002) showed that PD-L1 expressed on human tumours induced T-cell apoptosis.\n\nThese data motivated the development of nivolumab (Ono/Medarex) and other PD-1 and PD-L1 antibodies, now the most widely used cancer drugs in the world. Honjo shared the 2018 Nobel Prize with James Allison.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1073/pnas.192461099"},{"label":"Discovery of PD-1 (Ishida 1992)","url":"https://doi.org/10.1002/j.1460-2075.1992.tb05481.x"}],"tags":[],"related":["paper-leach-allison-ctla4-blockade-science-1996"],"cancers":[],"sections":["immunotherapy"],"technologies":["checkpoint-inhibitor"],"targets":["pd1","pdl1"],"drugs":["nivolumab","pembrolizumab","atezolizumab"],"companies":[],"institutions":[],"pathways":["pd1-checkpoint","antigen-presentation-immunoediting"],"terms":[],"trials":[],"people":["drew-pardoll","james-allison"],"bottlenecks":["b-immunotherapy-response","b-biomarker-validation"],"keyPapers":[],"journals":["pnas"],"dependsOn":[],"notes":[],"journal":"PNAS","year":2002,"doi":"10.1073/pnas.192461099","pmid":"12218188","authors":"Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N","paperType":"basic","findings":["PD-L1 expression on tumour cells reduced cytotoxic T-cell killing in vitro and enhanced tumour growth in mice","Anti-PD-L1 antibody suppressed growth of PD-L1-expressing tumours","Naturally PD-L1-positive myeloma cells were rejected in PD-1-deficient mice but not in wild-type mice","Together with Ishida 1992 and Freeman 2000, defined the PD-1/PD-L1 axis as a tumour immune-escape mechanism"],"whatItMeans":"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.","caveats":["Mouse tumour models overexpressing PD-L1 exaggerate a mechanism that is only one of many in human tumours","PD-L1 expression on tumour cells is an imperfect biomarker of response in patients","Most patients do not respond to PD-1 blockade, and mechanisms of primary resistance remain incompletely understood","Clinical translation took another decade and depended on industry (Ono, Medarex, BMS, Merck) investment"],"changedPractice":false},"route":"/key-papers/paper-iwai-pdl1-tumour-escape-pnas-2002/","neighbours":{"paper":[{"id":"paper-leach-allison-ctla4-blockade-science-1996","kind":"paper","name":"Leach, Krummel and Allison: releasing the CTLA-4 brake makes mice reject tumours","route":"/key-papers/paper-leach-allison-ctla4-blockade-science-1996/"}],"section":[{"id":"immunotherapy","kind":"section","name":"Immunotherapy","route":"/fronts/immunotherapy/"}],"technology":[{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"}],"target":[{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"},{"id":"pdl1","kind":"target","name":"PD-L1","route":"/targets/pdl1/"}],"drug":[{"id":"atezolizumab","kind":"drug","name":"Atezolizumab","route":"/drugs/atezolizumab/"},{"id":"nivolumab","kind":"drug","name":"Nivolumab","route":"/drugs/nivolumab/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"}],"pathway":[{"id":"antigen-presentation-immunoediting","kind":"pathway","name":"Antigen presentation & immune editing","route":"/pathways/antigen-presentation-immunoediting/"},{"id":"pd1-checkpoint","kind":"pathway","name":"PD-1 / PD-L1 immune checkpoint & T-cell activation","route":"/pathways/pd1-checkpoint/"}],"person":[{"id":"drew-pardoll","kind":"person","name":"Drew M. Pardoll","route":"/people/drew-pardoll/"},{"id":"james-allison","kind":"person","name":"James P. Allison","route":"/people/james-allison/"},{"id":"lieping-chen","kind":"person","name":"Lieping Chen","route":"/people/lieping-chen/"}],"bottleneck":[{"id":"b-biomarker-validation","kind":"bottleneck","name":"Biomarkers are not validated or standardised","route":"/bottlenecks/b-biomarker-validation/"},{"id":"b-immunotherapy-response","kind":"bottleneck","name":"No one can predict who responds to immunotherapy","route":"/bottlenecks/b-immunotherapy-response/"}],"journal":[{"id":"pnas","kind":"journal","name":"Proceedings of the National Academy of Sciences","route":"/journals/pnas/"}]}}