Upregulation of Tim-3 and PD-1 Expression is Associated with Tumor Antigen-Specific CD8\(^+\) T Cell Dysfunction in Melanoma Patients

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Upregulation of Tim-3 and PD-1 Expression is Associated with Tumor Antigen-Specific CD8\(^+\) T Cell Dysfunction in Melanoma Patients

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dc.contributor.author Fourcade, Julien
dc.contributor.author Sun, Zhaojun
dc.contributor.author Benallaoua, Mourad
dc.contributor.author Guillaume, Philippe
dc.contributor.author Luescher, Immanuel F.
dc.contributor.author Sander, Cindy
dc.contributor.author Kirkwood, John M.
dc.contributor.author Zarour, Hassane M.
dc.contributor.author Kuchroo, Vijay Kumar
dc.date.accessioned 2011-12-06T20:15:31Z
dc.date.issued 2010
dc.identifier.citation Fourcade, 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.issn 0022-1007 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:5361375
dc.description.abstract The 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.iso en_US en_US
dc.publisher The Rockefeller University Press en_US
dc.relation.isversionof doi://10.1084/jem.20100637 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947081/pdf/ en_US
dash.license LAA
dc.title Upregulation of Tim-3 and PD-1 Expression is Associated with Tumor Antigen-Specific CD8\(^+\) T Cell Dysfunction in Melanoma Patients en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal The Journal of Experimental Medicine en_US
dash.depositing.author Kuchroo, Vijay Kumar
dc.date.available 2011-12-06T20:15:31Z
dash.affiliation.other HMS^Neurology-Brigham and Women's Hospital en_US

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