{"entity":{"id":"paper-tumeh-pd1-adaptive-immune-resistance-nature-2014","kind":"paper","name":"Tumeh 2014: PD-1 blockade works by releasing T cells already present at the tumour edge","aka":[],"tldr":"Melanomas that responded to pembrolizumab already contained killer T cells pressed up against tumour cells expressing PD-L1, showing that the drug works by releasing an immune attack that is already there rather than creating a new one.","summary":"Tumeh, Ribas and colleagues at UCLA studied tumour biopsies from 46 patients with metastatic melanoma before and during pembrolizumab. Responding tumours had higher densities of CD8 T cells, PD-1 and PD-L1 at the invasive margin and in the tumour before treatment, with T cells and PD-L1 in close proximity, and their T cell receptor repertoires were more clonal and expanded further on treatment. The authors proposed that PD-L1 is induced as an adaptive resistance mechanism in response to interferon from attacking T cells and that pembrolizumab reverses it.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1038/nature13954"}],"tags":[],"related":["paper-rizvi-mutational-landscape-pd1-science-2015"],"cancers":["melanoma"],"sections":[],"technologies":[],"targets":["pd1","pdl1"],"drugs":["pembrolizumab"],"companies":[],"institutions":["ucla-jonsson"],"pathways":[],"terms":["tils","immune-checkpoint"],"trials":[],"people":["antoni-ribas"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Nature","year":2014,"doi":"10.1038/nature13954","authors":"Tumeh PC, Harview CL, Yearley JH, et al.","paperType":"translational","findings":["Serial biopsies from 46 melanoma patients treated with pembrolizumab.","Pre-treatment CD8 T cell density and PD-1 and PD-L1 expression at the invasive margin and in the tumour were higher in responders.","Responders showed more clonal T cell receptor repertoires that expanded during treatment.","A predictive model based on these features identified most responders in a validation set."],"whatItMeans":"This paper explained why PD-1 antibodies work in some patients and not others and introduced the idea of inflamed versus non-inflamed tumours that now guides combination strategies designed to bring T cells into cold tumours.","caveats":["Small cohort from a single centre.","Biopsies sample one site and may not represent all metastases."],"changedPractice":false,"participants":46},"route":"/key-papers/paper-tumeh-pd1-adaptive-immune-resistance-nature-2014/","neighbours":{"paper":[{"id":"paper-binnewies-tumor-immune-microenvironment-natmed-2018","kind":"paper","name":"Binnewies 2018: understanding the tumour immune microenvironment for effective therapy","route":"/key-papers/paper-binnewies-tumor-immune-microenvironment-natmed-2018/"},{"id":"paper-ribas-wolchok-checkpoint-blockade-science-2018","kind":"paper","name":"Ribas and Wolchok 2018: cancer immunotherapy using checkpoint blockade","route":"/key-papers/paper-ribas-wolchok-checkpoint-blockade-science-2018/"},{"id":"paper-rizvi-mutational-landscape-pd1-science-2015","kind":"paper","name":"Rizvi 2015: the mutational landscape determines who responds to PD-1 blockade in lung cancer","route":"/key-papers/paper-rizvi-mutational-landscape-pd1-science-2015/"}],"cancer":[{"id":"melanoma","kind":"cancer","name":"Melanoma","route":"/cancers/melanoma/"}],"target":[{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"},{"id":"pdl1","kind":"target","name":"PD-L1","route":"/targets/pdl1/"}],"drug":[{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"}],"institution":[{"id":"ucla-jonsson","kind":"institution","name":"UCLA Jonsson Comprehensive Cancer Center","route":"/institutions/ucla-jonsson/"}],"term":[{"id":"immune-checkpoint","kind":"term","name":"Immune checkpoint","route":"/terms/immune-checkpoint/"},{"id":"tils","kind":"term","name":"Tumour-infiltrating lymphocytes (TILs)","route":"/terms/tils/"}],"person":[{"id":"antoni-ribas","kind":"person","name":"Antoni Ribas","route":"/people/antoni-ribas/"}]}}