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.
引用
收藏
页码:1243 / +
页数:20
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