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

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

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