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n2:pmcid
PMC0
bibo:doi
10.1084%2Fjem.20100637
n5:contains
_:vb8655534 _:vb8655528
Subject Item
_:vb8655528
rdf:type
n5:Section
dc:title
results
n5:contains
_:vb8655532 _:vb8655533 _:vb8655529 _:vb8655530 _:vb8655531
Subject Item
_:vb8655529
rdf:type
n2:Context
rdf:value
As the majority of spontaneous NY-ESO-1–specific CD8+ T cells in melanoma patients up-regulates PD-1 expression (Fourcade et al., >>2009<<), we next determined whether Tim-3 and PD-1 are expressed on identical or distinct T cell subsets.
n2:mentions
n3:19380770
Subject Item
_:vb8655530
rdf:type
n2:Context
rdf:value
between Tim-3−PD-1+ and Tim-3−PD-1− NY-ESO-1–specific CD8+ T cells, confirming our previous findings that PD-1 up-regulation is not directly associated with an inability to produce cytokines upon ex vivo stimulation (Fourcade et al., >>2009<<). Strikingly, in one melanoma patient with very high levels of spontaneous NY-ESO-1–specific CD8+ T cells (Fig.
n2:mentions
n3:19380770
Subject Item
_:vb8655531
rdf:type
n2:Context
rdf:value
NY-ESO-1–specific CD8+ T cells (67 versus 81% and 49 versus 77%, respectively), suggesting that Tim-3 expression alone defines a population of dysfunctional T cells, as previously reported for HIV-specific CD8+ T cells (Jones et al., >>2008<<). Furthermore, we observed in the same patient that Tim-3+PD-1+ NY-ESO-1–specific CD8+ T cells produced less IFN-γ and TNF than Tim-3+PD-1− NY-ESO-1–specific CD8+ T cells (53% versus 67% and 27% versus 49%, respectively), suggesting that
n2:mentions
n3:19001139
Subject Item
_:vb8655532
rdf:type
n2:Context
rdf:value
In agreement with our previous findings, PD-1–PD-L1 blockade alone did not increase cytokine production by NY-ESO-1–specific CD8+ T cells upon short ex vivo stimulation with cognate peptide (Fourcade et al., >>2009<<). We observed no cytokine production by NY-ESO-1 157–165–specific CD8+ T cells after short ex vivo stimulation (6 h) with an irrelevant peptide with or without Tim-3 and/or PD-1 blockade (Fig. S3 A). We also observed that Tim-3 pathway
n2:mentions
n3:19380770
Subject Item
_:vb8655533
rdf:type
n2:Context
rdf:value
In line with previous findings (Fourcade et al., >>2009<<), PD-1–PD-L1 blockade in the presence of cognate peptide enhanced proliferating and total NY-ESO-1–specific CD8+ T cells (P = 0.0117 and P = 0.0039, respectively; Fig.
n2:mentions
n3:19380770
Subject Item
_:vb8655534
rdf:type
n5:Section
dc:title
discussion
n5:contains
_:vb8655536 _:vb8655537 _:vb8655538 _:vb8655539 _:vb8655535
Subject Item
_:vb8655535
rdf:type
n2:Context
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Therefore, unlike virus-specific CD8+ T cells evaluated in our study and HIV-specific CD8+ T cells (Jones et al., >>2008<<), spontaneous Tim-3+ NY-ESO-1–specific CD8+ T cells coexpress PD-1 in patients with advanced melanoma.
n2:mentions
n3:19001139
Subject Item
_:vb8655536
rdf:type
n2:Context
rdf:value
in line with our previous demonstration that PD-1 acts as a regulator of NY-ESO-1–specific CD8+ T cell expansion upon chronic antigen exposure and has no major impact on their functionality on a cell-per-cell basis (Fourcade et al., >>2009<<). In one melanoma patient with very high levels of spontaneous NY-ESO-1–specific CD8+ T cells, we found that Tim-3+PD-1− NY-ESO-1–specific CD8+ T cells produced less cytokines than Tim-3−PD-1− NY-ESO-1–specific CD8+ T cells, suggesting
n2:mentions
n3:19380770
Subject Item
_:vb8655537
rdf:type
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chronic persistent infections has shown that coexpression of multiple inhibitory receptors, including PD-1, LAG-3, 2B4, and CD160 by the same virus-specific CD8+ T cells was associated with lower T cell functions (Blackburn et al., >>2009<<). Our findings further add to this observation and support that coexpression of Tim-3 and PD-1 is a marker of tumor-induced T cell dysfunction in patients with advanced melanoma.
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These findings are in line with one study demonstrating the role of Tim-3 blockade in improving Tim-3+ HIV-specific CD8+ T cell functions (Jones et al., >>2008<<). Although we could not measure the percentages of cytokine-producing Tim-3+ NY-ESO-1–specific CD8+ T cells in wells containing the blocking anti–Tim-3 mAbs, it is tempting to speculate that the increased frequencies of cytokine-producing
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One caveat is the disruption of the Tim-3–Tim-3L pathway appears to contribute to autoimmunity (Koguchi et al., >>2006<<). Therefore, it will be critical to carefully monitor the occurrence of serious autoimmune side effects in vivo.
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