Ontology type: schema:ScholarlyArticle Open Access: True
2014-11
AUTHORSPaul C. Tumeh, Christina L. Harview, Jennifer H. Yearley, I. Peter Shintaku, Emma J. M. Taylor, Lidia Robert, Bartosz Chmielowski, Marko Spasic, Gina Henry, Voicu Ciobanu, Alisha N. West, Manuel Carmona, Christine Kivork, Elizabeth Seja, Grace Cherry, Antonio J. Gutierrez, Tristan R. Grogan, Christine Mateus, Gorana Tomasic, John A. Glaspy, Ryan O. Emerson, Harlan Robins, Robert H. Pierce, David A. Elashoff, Caroline Robert, Antoni Ribas
ABSTRACTTherapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types. One mechanism by which cancer tissues limit the host immune response is via upregulation of PD-1 ligand (PD-L1) and its ligation to PD-1 on antigen-specific CD8(+) T cells (termed adaptive immune resistance). Here we show that pre-existing CD8(+) T cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy. We analysed samples from 46 patients with metastatic melanoma obtained before and during anti-PD-1 therapy (pembrolizumab) using quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and next-generation sequencing for T-cell antigen receptors (TCRs). In serially sampled tumours, patients responding to treatment showed proliferation of intratumoral CD8(+) T cells that directly correlated with radiographic reduction in tumour size. Pre-treatment samples obtained from responding patients showed higher numbers of CD8-, PD-1- and PD-L1-expressing cells at the invasive tumour margin and inside tumours, with close proximity between PD-1 and PD-L1, and a more clonal TCR repertoire. Using multivariate analysis, we established a predictive model based on CD8 expression at the invasive margin and validated the model in an independent cohort of 15 patients. Our findings indicate that tumour regression after therapeutic PD-1 blockade requires pre-existing CD8(+) T cells that are negatively regulated by PD-1/PD-L1-mediated adaptive immune resistance. More... »
PAGES568
http://scigraph.springernature.com/pub.10.1038/nature13954
DOIhttp://dx.doi.org/10.1038/nature13954
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PUBMEDhttps://www.ncbi.nlm.nih.gov/pubmed/25428505
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]Download the RDF metadata as:Â json-ld nt turtle xml License info
JSON-LD is a popular format for linked data which is fully compatible with JSON.
curl -H 'Accept: application/ld+json' 'https://scigraph.springernature.com/pub.10.1038/nature13954'
N-Triples is a line-based linked data format ideal for batch operations.
curl -H 'Accept: application/n-triples' 'https://scigraph.springernature.com/pub.10.1038/nature13954'
Turtle is a human-readable linked data format.
curl -H 'Accept: text/turtle' 'https://scigraph.springernature.com/pub.10.1038/nature13954'
RDF/XML is a standard XML format for linked data.
curl -H 'Accept: application/rdf+xml' 'https://scigraph.springernature.com/pub.10.1038/nature13954'
This table displays all metadata directly associated to this object as RDF triples.
392 TRIPLES
21 PREDICATES
67 URIs
38 LITERALS
26 BLANK NODES