Siglec-9 acts as an immune checkpoint molecule on macrophages in glioblastoma, restricting T cell priming and immunotherapy response [scRNA-seq]
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ABSTRACT: The neoadjuvant immune checkpoint blockade therapy only benefits a limited fraction of glioblastoma multiforme (GBM) patients. Thus, targeting other immunomodulators on myeloid cells is an attractive therapeutic option. Here, we performed single-cell RNA sequencing and spatial transcriptomics of GBM patients treated with neoadjuvant anti-PD-1 therapy. We identified unique monocyte-derived tumor-associated macrophage (TAM) subpopulations with functional plasticity that highly expressed the immunosuppressive SIGLEC9 gene and preferentially accumulated in the non-responders to anti-PD-1 treatment. Deletion of Siglece (murine homologue) resulted in significantly restrained tumor development and prolonged survival in mouse models. Mechanistically, targeting Siglece directly activated both CD4+ T cells and CD8+ T cells through antigen presentation, secreted chemokines and co-stimulatory factor interactions. Furthermore, Siglece deletion synergized with anti-PD-1/PD-L1 treatment to improve antitumor efficacy. Our data demonstrated that Siglec-9 is an immune checkpoint molecule on macrophages that can be targeted to enhance anti-PD-1/PD-L1 therapeutic efficacy for GBM treatment.
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE235676 | GEO | 2023/06/29
REPOSITORIES: GEO
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