Immune Checkpoint Inhibitor-induced Reinvigoration of Tumor-infiltrating CD8(+) T Cells is Determined by Their Differentiation Status in Glioblastoma

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dc.contributor.authorPark, Junsikko
dc.contributor.authorKwon, Minsukko
dc.contributor.authorKim, Kyung Hwanko
dc.contributor.authorKim, Tae-Shinko
dc.contributor.authorHong, Seon-Huiko
dc.contributor.authorKim, Chang Gonko
dc.contributor.authorKang, Seok-Guko
dc.contributor.authorMoon, Ju Hyungko
dc.contributor.authorKim, Eui Hyunko
dc.contributor.authorPark, Su-Hyungko
dc.contributor.authorChang, Jong Heeko
dc.contributor.authorShin, Eui-Cheolko
dc.date.accessioned2020-01-21T06:20:54Z-
dc.date.available2020-01-21T06:20:54Z-
dc.date.created2020-01-21-
dc.date.issued2019-04-
dc.identifier.citationCLINICAL CANCER RESEARCH, v.25, no.8, pp.2549 - 2559-
dc.identifier.issn1078-0432-
dc.identifier.urihttp://hdl.handle.net/10203/271671-
dc.description.abstractPurpose: Immune checkpoint inhibitors (ICI) are used for the treatment of various cancers, but clinical trials of anti-programmed cell death protein 1 (PD-1) with patients with recurrent glioblastoma (GBM) have failed to show clinical benefits. In this study, we examined the differentiation status of CD8(+) tumor-infiltrating lymphocytes (TIL) from patients with primary GBM and their reinvigoration by ICIs to understand the nature of T-cell exhaustion in GBM. Experimental Design: We isolated TILs from 98 patients with newly diagnosed GBM and examined the expression of immune checkpoint receptors and T-cell transcription factors using flow cytometry. TILs were ex vivo stimulated with anti-CD3 in the presence of anti-PD-1 and/or anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) and their proliferation assessed. Results: CD8(+) TILs had significantly increased expression of immune checkpoint receptors, including PD-1 and CTLA-4, compared with peripheral blood CD8(+) T cells. Among CD8(+) TILs, PD-1(+) cells exhibited more terminally differentiated phenotypes (i.e., Eomes(hi)T-bet(lo)) than PD-1(-) cells. These data were confirmed by analyzing NY-ESO-1(157)-specific CD8(+) TILs. Evaluating the proliferation of CD8(+) TILs after ex vivo stimulation with anti-CD3 and anti-PD-1, we found that proliferation inversely correlated with the percentage of Eomes(hi)T-bet(lo) cells among PD-1(+) CD8(+) TILs. When anti-CTLA-4 was used in combination with anti-PD-1, an additional increase in CD8(+) TIL proliferation was observed in patients with low percentages of Eomes(hi)T-bet(lo) CD8(+) TILs, who responded well to anti-PD-1 in ex vivo assays, but not in patients with high percentages of Eomes(hi)T-bet(lo) CD8(+) TILs, who did not respond to anti-PD-1. Conclusions: In primary GBM, the differentiation status of CD8(+) TILs determines their reinvigoration ability upon ICI treatment.-
dc.languageEnglish-
dc.publisherAMER ASSOC CANCER RESEARCH-
dc.titleImmune Checkpoint Inhibitor-induced Reinvigoration of Tumor-infiltrating CD8(+) T Cells is Determined by Their Differentiation Status in Glioblastoma-
dc.typeArticle-
dc.identifier.wosid000464654200022-
dc.identifier.scopusid2-s2.0-85064902756-
dc.type.rimsART-
dc.citation.volume25-
dc.citation.issue8-
dc.citation.beginningpage2549-
dc.citation.endingpage2559-
dc.citation.publicationnameCLINICAL CANCER RESEARCH-
dc.identifier.doi10.1158/1078-0432.CCR-18-2564-
dc.contributor.localauthorPark, Su-Hyung-
dc.contributor.localauthorShin, Eui-Cheol-
dc.contributor.nonIdAuthorKim, Tae-Shin-
dc.contributor.nonIdAuthorKim, Chang Gon-
dc.contributor.nonIdAuthorKang, Seok-Gu-
dc.contributor.nonIdAuthorMoon, Ju Hyung-
dc.contributor.nonIdAuthorKim, Eui Hyun-
dc.contributor.nonIdAuthorChang, Jong Hee-
dc.description.isOpenAccessN-
dc.type.journalArticleArticle-
dc.subject.keywordPlusPRIMARY BRAIN-
dc.subject.keywordPlusNIVOLUMAB-
dc.subject.keywordPlusBLOCKADE-
dc.subject.keywordPlusSAFETY-
dc.subject.keywordPlusIMMUNOTHERAPY-
dc.subject.keywordPlusEXPRESSION-
dc.subject.keywordPlusPROLIFERATION-
dc.subject.keywordPlusIPILIMUMAB-
dc.subject.keywordPlusEXHAUSTION-
dc.subject.keywordPlusRESPONSES-
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