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A case report of clonal EBV-like memory CD4+ T cell activation in fatal checkpoint inhibitor-induced encephalitis
- Source :
- Nature Medicine. 25:1243-1250
- Publication Year :
- 2019
- Publisher :
- Springer Science and Business Media LLC, 2019.
-
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.
- Subjects :
- 0301 basic medicine
business.industry
Fulminant
T-cell receptor
General Medicine
medicine.disease
General Biochemistry, Genetics and Molecular Biology
GZMB
03 medical and health sciences
030104 developmental biology
0302 clinical medicine
Immune system
030220 oncology & carcinogenesis
Cancer research
Cytotoxic T cell
Medicine
business
Receptor
CD8
Encephalitis
Subjects
Details
- ISSN :
- 1546170X and 10788956
- Volume :
- 25
- Database :
- OpenAIRE
- Journal :
- Nature Medicine
- Accession number :
- edsair.doi...........c627227be1cd83e714203554c40967a9