A case report of clonal EBV-like memory CD4+ T cell activation in fatal checkpoint inhibitor-induced encephalitis.
IF: 87.241
Cited by: 123


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.


Spatial Omics
Spatial Gene Expression

MeSH terms

Aged, 80 and over
CD4-Positive T-Lymphocytes
Herpesvirus 4, Human
Immunologic Memory
Lymphocyte Activation
Middle Aged
Programmed Cell Death 1 Receptor
Young Adult


Johnson, Douglas B
McDonnell, Wyatt J
Gonzalez-Ericsson, Paula I
Al-Rohil, Rami N
Mobley, Bret C
Salem, Joe-Elie
Wang, Daniel Y
Sanchez, Violeta
Wang, Yu
Chastain, Cody A
Barker, Kristi
Liang, Yan
Warren, Sarah
Beechem, Joseph M
Menzies, Alexander M
Tio, Martin
Long, Georgina V
Cohen, Justine V
Guidon, Amanda C
O'Hare, Méabh
Chandra, Sunandana
Chowdhary, Akansha
Lebrun-Vignes, Bénédicte
Goldinger, Simone M
Rushing, Elisabeth J
Buchbinder, Elizabeth I
Mallal, Simon A
Shi, Chanjuan
Xu, Yaomin
Moslehi, Javid J
Sanders, Melinda E
Sosman, Jeffrey A
Balko, Justin M

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