Siglec-9 acts as an immune-checkpoint molecule on macrophages in glioblastoma, restricting T-cell priming and immunotherapy response
© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc..
Neoadjuvant immune-checkpoint blockade therapy only benefits a limited fraction of patients with glioblastoma multiforme (GBM). Thus, targeting other immunomodulators on myeloid cells is an attractive therapeutic option. Here, we performed single-cell RNA sequencing and spatial transcriptomics of patients with GBM treated with neoadjuvant anti-PD-1 therapy. We identified unique monocyte-derived tumor-associated macrophage subpopulations with functional plasticity that highly expressed the immunosuppressive SIGLEC9 gene and preferentially accumulated in the nonresponders to anti-PD-1 treatment. Deletion of Siglece (murine homolog) resulted in dramatically 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.
| Errataetall: |
CommentIn: Nat Cancer. 2023 Sep;4(9):1217-1219. - PMID 37500790 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:4 |
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| Enthalten in: |
Nature cancer - 4(2023), 9 vom: 17. Sept., Seite 1273-1291 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Mei, Yan [VerfasserIn] |
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| Links: |
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| Themen: |
B7-H1 Antigen |
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| Anmerkungen: |
Date Completed 05.10.2023 Date Revised 16.10.2023 published: Print-Electronic figshare: 10.6084/m9.figshare.22434341 CommentIn: Nat Cancer. 2023 Sep;4(9):1217-1219. - PMID 37500790 Citation Status MEDLINE |
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| doi: |
10.1038/s43018-023-00598-9 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM359614248 |
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| 500 | |a CommentIn: Nat Cancer. 2023 Sep;4(9):1217-1219. - PMID 37500790 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023. The Author(s), under exclusive licence to Springer Nature America, Inc. | ||
| 520 | |a Neoadjuvant immune-checkpoint blockade therapy only benefits a limited fraction of patients with glioblastoma multiforme (GBM). Thus, targeting other immunomodulators on myeloid cells is an attractive therapeutic option. Here, we performed single-cell RNA sequencing and spatial transcriptomics of patients with GBM treated with neoadjuvant anti-PD-1 therapy. We identified unique monocyte-derived tumor-associated macrophage subpopulations with functional plasticity that highly expressed the immunosuppressive SIGLEC9 gene and preferentially accumulated in the nonresponders to anti-PD-1 treatment. Deletion of Siglece (murine homolog) resulted in dramatically 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 | ||
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| 700 | 1 | |a He, Junjie |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Chunliu |e verfasserin |4 aut | |
| 700 | 1 | |a Liao, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yingzhao |e verfasserin |4 aut | |
| 700 | 1 | |a Feng, Yongyi |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Hongyu |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Xiuying |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Lingdan |e verfasserin |4 aut | |
| 700 | 1 | |a Yi, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Xi |e verfasserin |4 aut | |
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| 700 | 1 | |a Wang, Xinyu |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yiyi |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Lixiang |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Zhigang |e verfasserin |4 aut | |
| 700 | 1 | |a Ren, Xianwen |e verfasserin |4 aut | |
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| 700 | 1 | |a Chen, Jun |e verfasserin |4 aut | |
| 700 | 1 | |a Jia, Guangshuai |e verfasserin |4 aut | |
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