期刊
NATURE MEDICINE
卷 25, 期 8, 页码 1243-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41591-019-0523-2
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资金
- NHBLI [T32HL069765]
- NIDDK [R01DK112262, R56DK108352]
- NHLBI [K12HL143956]
- NIAID [P30AI110527]
- NIH/NCI [K23 CA204726, R00CA181491]
- James C. Bradford Jr. Melanoma Fund
- Cancer ITMO of the French National Alliance for Life and Health Sciences (AVIESAN)
- Department of Defense Era of Hope Award [BC170037]
- NCI/NIH Cancer Center [5P30 CA68485-19]
- Vanderbilt Mouse Metabolic Phenotyping Center [2 U24 DK059637-16]
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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