http://purl.uniprot.org/citations/31636098 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
http://purl.uniprot.org/citations/31636098 | http://www.w3.org/2000/01/rdf-schema#comment | "PurposeResponse rates to immune checkpoint blockade (ICB; anti-PD-1/anti-CTLA-4) correlate with the extent of tumor immune infiltrate, but the mechanisms underlying the recruitment of T cells following therapy are poorly characterized. A greater understanding of these processes may see the development of therapeutic interventions that enhance T-cell recruitment and, consequently, improved patient outcomes. We therefore investigated the chemokines essential for immune cell recruitment and subsequent therapeutic efficacy of these immunotherapies.Experimental designThe chemokines upregulated by dual PD-1/CTLA-4 blockade were assessed using NanoString-based analysis with results confirmed at the protein level by flow cytometry and cytometric bead array. Blocking/neutralizing antibodies confirmed the requirement for key chemokines/cytokines and immune effector cells. Results were confirmed in patients treated with immune checkpoint inhibitors using single-cell RNA-sequencing (RNA-seq) and paired survival analyses.ResultsThe CXCR3 ligands, CXCL9 and CXCL10, were significantly upregulated following dual PD-1/CTLA-4 blockade and both CD8+ T-cell infiltration and therapeutic efficacy were CXCR3 dependent. In both murine models and patients undergoing immunotherapy, macrophages were the predominant source of CXCL9 and their depletion abrogated CD8+ T-cell infiltration and the therapeutic efficacy of dual ICB. Single-cell RNA-seq analysis of patient tumor-infiltrating lymphocytes (TIL) revealed that CXCL9/10/11 was predominantly expressed by macrophages following ICB and we identified a distinct macrophage signature that was associated with positive responses to ICB.ConclusionsThese data underline the fundamental importance of macrophage-derived CXCR3 ligands for the therapeutic efficacy of ICB and highlight the potential of manipulating this axis to enhance patient responses."xsd:string |
http://purl.uniprot.org/citations/31636098 | http://purl.org/dc/terms/identifier | "doi:10.1158/1078-0432.ccr-19-1868"xsd:string |
http://purl.uniprot.org/citations/31636098 | http://purl.uniprot.org/core/author | "Lai J."xsd:string |
http://purl.uniprot.org/citations/31636098 | http://purl.uniprot.org/core/author | "Darcy P.K."xsd:string |
http://purl.uniprot.org/citations/31636098 | http://purl.uniprot.org/core/author | "Beavis P.A."xsd:string |
http://purl.uniprot.org/citations/31636098 | http://purl.uniprot.org/core/author | "Henderson M.A."xsd:string |
http://purl.uniprot.org/citations/31636098 | http://purl.uniprot.org/core/author | "Teo Z.L."xsd:string |
http://purl.uniprot.org/citations/31636098 | http://purl.uniprot.org/core/author | "Long G.V."xsd:string |
http://purl.uniprot.org/citations/31636098 | http://purl.uniprot.org/core/author | "Scolyer R.A."xsd:string |
http://purl.uniprot.org/citations/31636098 | http://purl.uniprot.org/core/author | "Savas P."xsd:string |
http://purl.uniprot.org/citations/31636098 | http://purl.uniprot.org/core/author | "Loi S."xsd:string |
http://purl.uniprot.org/citations/31636098 | http://purl.uniprot.org/core/author | "Todd K.L."xsd:string |
http://purl.uniprot.org/citations/31636098 | http://purl.uniprot.org/core/author | "Wilmott J.S."xsd:string |
http://purl.uniprot.org/citations/31636098 | http://purl.uniprot.org/core/author | "Giuffrida L."xsd:string |
http://purl.uniprot.org/citations/31636098 | http://purl.uniprot.org/core/author | "House I.G."xsd:string |
http://purl.uniprot.org/citations/31636098 | http://purl.uniprot.org/core/author | "Mardiana S."xsd:string |
http://purl.uniprot.org/citations/31636098 | http://purl.uniprot.org/core/author | "Gide T.N."xsd:string |
http://purl.uniprot.org/citations/31636098 | http://purl.uniprot.org/core/author | "Quek C."xsd:string |
http://purl.uniprot.org/citations/31636098 | http://purl.uniprot.org/core/author | "Chen A.X.Y."xsd:string |
http://purl.uniprot.org/citations/31636098 | http://purl.uniprot.org/core/author | "Oliver A.J."xsd:string |
http://purl.uniprot.org/citations/31636098 | http://purl.uniprot.org/core/author | "Petley E.V."xsd:string |
http://purl.uniprot.org/citations/31636098 | http://purl.uniprot.org/core/author | "Sek K."xsd:string |
http://purl.uniprot.org/citations/31636098 | http://purl.uniprot.org/core/date | "2020"xsd:gYear |
http://purl.uniprot.org/citations/31636098 | http://purl.uniprot.org/core/name | "Clin Cancer Res"xsd:string |