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- Title
Anti–PD-1 cancer immunotherapy induces central nervous system immune-related adverse events by microglia activation.
- Authors
Vinnakota, Janaki Manoja; Adams, Rachael C.; Athanassopoulos, Dimitrios; Schmidt, Dominik; Biavasco, Francesca; Zähringer, Alexander; Erny, Daniel; Schwabenland, Marius; Langenbach, Marlene; Wenger, Valentin; Salié, Henrike; Cook, James; Mossad, Omar; Andrieux, Geoffroy; Dersch, Rick; Rauer, Sebastian; Duquesne, Sandra; Monaco, Gianni; Wolf, Phillipp; Blank, Thomas
- Abstract
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. Editor's summary: Immune checkpoint inhibitors targeting PD-1 and CTLA-4 have revolutionized cancer treatment, but these powerful treatments come at a cost. A subset of patients who receive these therapies develop immune-related adverse events (irAEs). These irAEs can affect multiple tissues, including the central nervous system (CNS). Here, Vinnakota et al. studied the CNS after PD-1 blockade in mice with and without tumors. The authors observed activation of microglia that was associated with behavioral changes. Preventing microglial activation with an inhibitor of Syk improved neurocognitive functions in mice cotreated with PD-1 blockade. Finally, the authors showed that CNS tissue from patients who received PD-1 blockade also had evidence of microglial activation. Together, these data suggest both a cause of CNS-irAEs and a potential therapeutic approach. —Courtney Malo
- Subjects
DRUG side effects; CENTRAL nervous system; MICROGLIA; KILLER cells; IMMUNE checkpoint inhibitors
- Publication
Science Translational Medicine, 2024, Vol 16, Issue 751, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.adj9672