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

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 histoc...

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Published in:	Science translational medicine Vol. 16; no. 751; p. eadj9672
Main 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, Häne, Philipp, Greter, Melanie, Becher, Burkhard, Henneke, Philipp, Pfeifer, Dietmar, Blazar, Bruce R, Duyster, Justus, Boerries, Melanie, Köhler, Natalie, Chhatbar, Chintan M, Bengsch, Bertram, Prinz, Marco, Zeiser, Robert
Format:	Journal Article
Language:	English
Published:	United States 12-06-2024
Subjects:	Animals Central Nervous System - drug effects Central Nervous System - pathology Humans Immunotherapy - adverse effects Mice Mice, Inbred C57BL Microglia - drug effects Microglia - metabolism Microglia - pathology Programmed Cell Death 1 Receptor - antagonists & inhibitors Programmed Cell Death 1 Receptor - metabolism Syk Kinase - metabolism
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Summary:	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.
ISSN:	1946-6242
DOI:	10.1126/scitranslmed.adj9672