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dc.contributor.authorFourcade, Julien
dc.contributor.authorSun, Zhaojun
dc.contributor.authorBenallaoua, Mourad
dc.contributor.authorGuillaume, Philippe
dc.contributor.authorLuescher, Immanuel F.
dc.contributor.authorSander, Cindy
dc.contributor.authorKirkwood, John M.
dc.contributor.authorKuchroo, Vijay Kumar
dc.contributor.authorZarour, Hassane M.
dc.date.accessioned2011-12-06T20:15:31Z
dc.date.issued2010
dc.identifier.citationFourcade, Julien, Zhaojun Sun, Mourad Benallaoua, Philippe Guillaume, Immanuel F. Luescher, Cindy Sander, John M. Kirkwood, Vijay Kuchroo, and Hassane M. Zarour. 2010. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8\(^+\) T cell dysfunction in melanoma patients. The Journal of Experimental Medicine 207(10): 2175-2186.en_US
dc.identifier.issn0022-1007en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:5361375
dc.description.abstractThe paradoxical coexistence of spontaneous tumor antigen–specific immune responses with progressive disease in cancer patients furthers the need to dissect the molecular pathways involved in tumor-induced T cell dysfunction. In patients with advanced melanoma, we have previously shown that the cancer-germline antigen NY-ESO-1 stimulates spontaneous NY-ESO-1–specific CD8\(^+\) T cells that up-regulate PD-1 expression. We also observed that PD-1 regulates NY-ESO-1–specific CD8\(^+\) T cell expansion upon chronic antigen stimulation. In the present study, we show that a fraction of PD-1\(^+\) NY-ESO-1–specific CD8\(^+\) T cells in patients with advanced melanoma up-regulates Tim-3 expression and that Tim-3\(^+\)PD-1\(^+\) NY-ESO-1–specific CD8\(^+\) T cells are more dysfunctional than Tim-3\(^-\)PD-1\(^+\) and Tim-3\(^-\)PD-1\(^-\) NY-ESO-1–specific CD8\(^+\) T cells, producing less IFN-γ, TNF, and IL-2. Tim-3–Tim-3L block- ade enhanced cytokine production by NY-ESO-1–specific CD8\(^+\) T cells upon short ex vivo stimulation with cognate peptide, thus enhancing their functional capacity. In addition, Tim-3–Tim-3L blockade enhanced cytokine production and proliferation of NY-ESO-1– specific CD8\(^+\) T cells upon prolonged antigen stimulation and acted in synergy with PD-1– PD-L1 blockade. Collectively, our findings support the use of Tim-3–Tim-3L blockade together with PD-1–PD-L1 blockade to reverse tumor-induced T cell exhaustion/dysfunction in patients with advanced melanoma.en_US
dc.language.isoen_USen_US
dc.publisherThe Rockefeller University Pressen_US
dc.relation.isversionofdoi://10.1084/jem.20100637en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947081/pdf/en_US
dash.licenseLAA
dc.titleUpregulation of Tim-3 and PD-1 Expression is Associated with Tumor Antigen-Specific CD8\(^+\) T Cell Dysfunction in Melanoma Patientsen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalThe Journal of Experimental Medicineen_US
dash.depositing.authorKuchroo, Vijay Kumar
dc.date.available2011-12-06T20:15:31Z
dash.affiliation.otherHMS^Neurology-Brigham and Women's Hospitalen_US
dc.identifier.doi10.1084/jem.20100637*
dash.contributor.affiliatedKuchroo, Vijay


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