%0 Journal Article
%T Anti-PD-1 cancer immunotherapy induces central nervous system immune-related adverse events by microglia activation.
%A Vinnakota JM
%A Adams RC
%A Athanassopoulos D
%A Schmidt D
%A Biavasco F
%A Zähringer A
%A Erny D
%A Schwabenland M
%A Langenbach M
%A Wenger V
%A Salié H
%A Cook J
%A Mossad O
%A Andrieux G
%A Dersch R
%A Rauer S
%A Duquesne S
%A Monaco G
%A Wolf P
%A Blank T
%A Häne P
%A Greter M
%A Becher B
%A Henneke P
%A Pfeifer D
%A Blazar BR
%A Duyster J
%A Boerries M
%A Köhler N
%A Chhatbar CM
%A Bengsch B
%A Prinz M
%A Zeiser R
%J Sci Transl Med
%V 16
%N 751
%D 2024 Jun 12
%M 38865481
%F 19.319
%R 10.1126/scitranslmed.adj9672
%X Cancer treatment with anti-PD-1 immunotherapy can cause central nervous system immune-related adverse events (CNS-irAEs). The role of microglia in anti-PD-1 immunotherapy-induced CNS-irAEs is unclear. We found that anti-PD-1 treatment of mice caused morphological signs of activation and major histocompatibility complex (MHC) class II up-regulation on microglia. Functionally, anti-PD-1 treatment induced neurocognitive deficits in mice, independent of T cells, B cells, and natural killer cells. Instead, we found that microglia mediated these CNS-irAEs. Single-cell RNA sequencing revealed major transcriptional changes in microglia upon anti-PD-1 treatment. The anti-PD-1 effects were mediated by anti-PD-1 antibodies interacting directly with microglia and were not secondary to peripheral T cell activation. Using a proteomics approach, we identified spleen tyrosine kinase (Syk) as a potential target in activated microglia upon anti-PD-1 treatment. Syk inhibition reduced microglia activation and improved neurocognitive function without impairing anti-melanoma effects. Moreover, we analyzed CNS tissue from a patient cohort that had received anti-PD-1 treatment. Imaging mass cytometry revealed that anti-PD-1 treatment of patients was associated with increased surface marker expression indicative of microglia activation. In summary, we identified a disease-promoting role for microglia in CNS-irAEs driven by Syk and provide an inhibitor-based approach to interfere with this complication after anti-PD-1 immunotherapy.