{Reference Type}: Journal Article
{Title}: Anti-PD-1 cancer immunotherapy induces central nervous system immune-related adverse events by microglia activation.
{Author}: Vinnakota JM;Adams RC;Athanassopoulos D;Schmidt D;Biavasco F;Zähringer A;Erny D;Schwabenland M;Langenbach M;Wenger V;Salié H;Cook J;Mossad O;Andrieux G;Dersch R;Rauer S;Duquesne S;Monaco G;Wolf P;Blank T;Häne P;Greter M;Becher B;Henneke P;Pfeifer D;Blazar BR;Duyster J;Boerries M;Köhler N;Chhatbar CM;Bengsch B;Prinz M;Zeiser R;
{Journal}: Sci Transl Med
{Volume}: 16
{Issue}: 751
{Year}: 2024 Jun 12
{Factor}: 19.319
{DOI}: 10.1126/scitranslmed.adj9672
{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.