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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; Häne, Philipp; Greter, Melanie; Becher, Burkhard; Henneke, Philipp; [...]

Anti–PD-1 cancer immunotherapy induces central nervous system immune-related adverse events by microglia activation

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  • Media type: E-Article
  • Title: Anti–PD-1 cancer immunotherapy induces central nervous system immune-related adverse events by microglia activation
  • Contributor: 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; Häne, Philipp; Greter, Melanie; Becher, Burkhard; Henneke, Philipp; [...]
  • Published: American Association for the Advancement of Science (AAAS), 2024
  • Published in: Science Translational Medicine, 16 (2024) 751
  • Language: English
  • DOI: 10.1126/scitranslmed.adj9672
  • ISSN: 1946-6234; 1946-6242
  • Origination:
  • Footnote:
  • Description: 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.