共 45 条
A case report of clonal EBV-like memory CD4+ T cell activation in fatal checkpoint inhibitor-induced encephalitis
被引:136
作者:
Johnson, Douglas B.
[1
,2
]
McDonnell, Wyatt J.
[1
,2
,3
,4
,5
]
Gonzalez-Ericsson, Paula I.
[6
]
Al-Rohil, Rami N.
[3
,7
]
Mobley, Bret C.
[3
]
Salem, Joe-Elie
[1
,8
]
Wang, Daniel Y.
[1
]
Sanchez, Violeta
[3
]
Wang, Yu
[9
]
Chastain, Cody A.
[1
]
Barker, Kristi
[10
]
Liang, Yan
[10
]
Warren, Sarah
[10
]
Beechem, Joseph M.
[10
]
Menzies, Alexander M.
[11
,12
,13
,14
]
Tio, Martin
[11
]
Long, Georgina V.
[11
,12
,13
,14
]
Cohen, Justine V.
[15
]
Guidon, Amanda C.
[15
]
O'Hare, Meabh
[15
]
Chandra, Sunandana
[16
]
Chowdhary, Akansha
[16
]
Lebrun-Vignes, Benedicte
[8
]
Goldinger, Simone M.
[17
]
Rushing, Elisabeth J.
[18
]
Buchbinder, Elizabeth I.
[19
]
Mallal, Simon A.
[1
,2
,3
,4
,20
]
Shi, Chanjuan
[3
]
Xu, Yaomin
[9
]
Moslehi, Javid J.
[1
]
Sanders, Melinda E.
[3
]
Sosman, Jeffrey A.
[21
]
Balko, Justin M.
[1
,2
,3
,6
]
机构:
[1] Vanderbilt Univ, Med Ctr, Dept Med, 221 Kirkland Hall, Nashville, TN 37235 USA
[2] Vanderbilt Univ, Med Ctr, Vanderbilt Inst Infect Immunol & Inflammat, 221 Kirkland Hall, Nashville, TN 37235 USA
[3] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, 221 Kirkland Hall, Nashville, TN 37235 USA
[4] Vanderbilt Univ, Med Ctr, Ctr Translat Immunol & Infect Dis, 221 Kirkland Hall, Nashville, TN 37235 USA
[5] Vanderbilt Univ, Med Ctr, Vanderbilt Vaccine Ctr, 221 Kirkland Hall, Nashville, TN 37235 USA
[6] Vanderbilt Univ, Med Ctr, Breast Canc Res Program, 221 Kirkland Hall, Nashville, TN 37235 USA
[7] Duke Univ, Med Ctr, Dept Pathol & Dermatol, Durham, NC USA
[8] Sorbonne Univ, Pitie Salpetriere Hosp, AP HP,Dept Pharmacol, INSERM CIC Paris Est,ICAN,Reg Pharmacovigilance C, Paris, France
[9] Vanderbilt Univ, Med Ctr, Dept Biostat, 221 Kirkland Hall, Nashville, TN 37235 USA
[10] NanoString Technol, Seattle, WA USA
[11] Melanoma Inst Australia, Sydney, NSW, Australia
[12] Univ Sydney, Sydney, NSW, Australia
[13] Royal North Shore Hosp, Sydney, NSW, Australia
[14] Mater Hosp, Sydney, NSW, Australia
[15] Massachusetts Gen Hosp, Boston, MA 02114 USA
[16] Northwestern Univ, Feinberg Sch Med, Evanston, IL USA
[17] Univ Hosp, Dept Dermatol, Zurich, Switzerland
[18] Univ Hosp, Inst Neuropathol, Zurich, Switzerland
[19] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA
[20] Inst Immunol & Infect Dis, Perth, WA, Australia
[21] Northwestern Feinberg Sch Med, Chicago, IL USA
关键词:
CLASS-I;
TCR REPERTOIRES;
CASE SERIES;
IPILIMUMAB;
EXPRESSION;
RESPONSES;
MELANOMA;
FEATURES;
DISTINCT;
EPITOPE;
D O I:
10.1038/s41591-019-0523-2
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
摘要:
Checkpoint inhibitors produce durable responses in numerous metastatic cancers, but immune-related adverse events (irAEs) complicate and limit their benefit. IrAEs can affect organ systems idiosyncratically; presentations range from mild and self-limited to fulminant and fatal. The molecular mechanisms underlying irAEs are poorly understood. Here, we report a fatal case of encephalitis arising during anti-programmed cell death receptor 1 therapy in a patient with metastatic melanoma. Histologic analyses revealed robust T cell infiltration and prominent programmed death ligand 1 expression. We identified 209 reported cases in global pharmacovigilance databases (across multiple cancer types) of encephalitis associated with checkpoint inhibitor regimens, with a 19% fatality rate. We performed further analyses from the index case and two additional cases to shed light on this recurrent and fulminant irAE. Spatial and multi-omic analyses pinpointed activated memory CD4(+) T cells as highly enriched in the inflamed, affected region. We identified a highly oligoclonal T cell receptor repertoire, which we localized to activated memory cytotoxic (CD45RO(+)GZMB(+)Ki67(+)) CD4 cells. We also identified Epstein-Barr virus-specific T cell receptors and EBV+ lymphocytes in the affected region, which we speculate contributed to neural inflammation in the index case. Collectively, the three cases studied here identify CD4(+) and CD8(+) T cells as culprits of checkpoint inhibitor-associated immune encephalitis.
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页码:1243 / +
页数:20
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