Abstract:
: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.
journal_name
Nat Medjournal_title
Nature medicineauthors
Johnson DB,McDonnell WJ,Gonzalez-Ericsson PI,Al-Rohil RN,Mobley BC,Salem JE,Wang DY,Sanchez V,Wang Y,Chastain CA,Barker K,Liang Y,Warren S,Beechem JM,Menzies AM,Tio M,Long GV,Cohen JV,Guidon AC,O'Hare M,Chandra Sdoi
10.1038/s41591-019-0523-2subject
Has Abstractpub_date
2019-08-01 00:00:00pages
1243-1250issue
8eissn
1078-8956issn
1546-170Xpii
10.1038/s41591-019-0523-2journal_volume
25pub_type
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