학술논문
Siglec-9 acts as an immune-checkpoint molecule on macrophages in glioblastoma, restricting T-cell priming and immunotherapy response
Document Type
Original Paper
Author
Mei, Yan; Wang, Xiumei; Zhang, Ji; Liu, Dan; He, Junjie; Huang, Chunliu; Liao, Jing; Wang, Yingzhao; Feng, Yongyi; Li, Hongyu; Liu, Xiuying; Chen, Lingdan; Yi, Wei; Chen, Xi; Bai, Hong-Min; Wang, Xinyu; Li, Yiyi; Wang, Lixiang; Liang, Zhigang; Ren, Xianwen; Qiu, Li; Hui, Yuan; Zhang, Qingling; Leng, Qibin; Chen, Jun; Jia, Guangshuai
Source
Nature Cancer. 4(9):1273-1291
Subject
Language
English
ISSN
2662-1347
Abstract
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.
Jia and colleagues profile human glioblastoma samples and identify a population of macrophages characterized by Siglec-9 that drives immune evasion and immunotherapy resistance via restriction of T-cell priming. Their therapeutic elimination synergizes with immunotherapy.
Jia and colleagues profile human glioblastoma samples and identify a population of macrophages characterized by Siglec-9 that drives immune evasion and immunotherapy resistance via restriction of T-cell priming. Their therapeutic elimination synergizes with immunotherapy.