Siglec-9 acts as an immune-checkpoint molecule on macrophages in glioblastoma, restricting T-cell priming and immunotherapy response

Mei, Yan1,2; Wang, Xiumei3,4; Zhang, Ji5; Liu, Dan6,7,8; He, Junjie1,6,8; Huang, Chunliu3,4; Liao, Jing9; Wang, Yingzhao10; Feng, Yongyi3,4; Li, Hongyu4; Liu, Xiuying11; Chen, Lingdan12; Yi, Wei13; Chen, Xi14; Bai, Hong-Min15; Wang, Xinyu3,4; Li, Yiyi3,4; Wang, Lixiang3,4; Liang, Zhigang1; Ren, Xianwen11; Qiu, Li1; Hui, Yuan1; Zhang, Qingling2; Leng, Qibin1; Chen, Jun3,4,16,17; Jia, Guangshuai1,6,8

2023-07-01

10.1038/s43018-023-00598-9

NATURE CANCER   影响因子和分区

2662-1347

["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."]

SCI

英语

ESI高被引

其他

National Key Ramp;D Program of China["2019YFA0110300","2020YFA0509400"] ; National Natural Science Foundation of China["82203538","82150117","82071745","82130076","81972668","31900570","82101329"] ; High-level Hospital Construction Project["DFJHBF202108","YKY-KF202204"] ; Guangdong Provincial Key Laboratory of Artificial Intelligence in Medical Image Analysis and Application[2022B1212010011] ; Guangdong Project[2019QN01Y212]

Oncology

Oncology

WOS:001031421300001

NATURE PORTFOLIO

Web of Science

1.Guangzhou Med Univ, Affiliated Canc Hosp & Inst, GMU GIBH Joint Sch Life Sci, State Key Lab Resp Dis, Guangzhou, Peoples R China
2.Southern Med Univ, Guangdong Prov Peoples Hosp, Guangdong Acad Med Sci, Dept Pathol, Guangzhou, Peoples R China
3.Sun Yat sen Univ, Zhongshan Sch Med, Dept Immunol & Microbiol, Guangzhou, Peoples R China
4.Sun Yat sen Univ, Guangdong Engn & Technol Res Ctr Dis Model Anim, Lab Anim Ctr, Zhongshan Sch Med, Guangzhou, Peoples R China
5.Sun Yat sen Univ, Collaborat Innovat Ctr Canc Med, Dept Neurosurg, State Key Lab Oncol South China,Canc Ctr, Guangzhou, Peoples R China
6.Xuzhou Med Univ, Canc Inst, Xuzhou, Peoples R China
7.Xuzhou Med Univ, Ctr Clin Oncol, Ctr Clin Oncol, Xuzhou, Peoples R China
8.Xuzhou Med Univ, Canc Inst, Jiangsu Ctr Collaborat & Innovat Canc Biotherapy, Xuzhou, Peoples R China
9.Guangzhou Med Univ, GMU GIBH Joint Sch Life Sci, Guangzhou, Peoples R China
10.Sun Yat sen Univ, Affiliated Hosp 1, Dept Gastrointestinal Surg, Guangzhou, Peoples R China
11.Changping Lab, Beijing, Peoples R China
12.Guangzhou Med Univ, Affiliated Hosp 1, Guangzhou, Peoples R China
13.Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, State Key Lab Ophthalmol, Guangzhou, Peoples R China
14.Southern Univ Sci & Technol, Dept Biol, Shenzhen, Peoples R China
15.Gen Hosp Southern Theater Command, Dept Neurosurg, Guangzhou, Peoples R China
16.Sun Yat sen Univ, Key Lab Trop Dis Control, Minist Educ, Guangzhou, Peoples R China
17.Jinfeng Lab, Chongqing, Peoples R China

Mei, Yan,Wang, Xiumei,Zhang, Ji,et al. Siglec-9 acts as an immune-checkpoint molecule on macrophages in glioblastoma, restricting T-cell priming and immunotherapy response[J]. NATURE CANCER,2023,4(9).

Mei, Yan.,Wang, Xiumei.,Zhang, Ji.,Liu, Dan.,He, Junjie.,...&Jia, Guangshuai.(2023).Siglec-9 acts as an immune-checkpoint molecule on macrophages in glioblastoma, restricting T-cell priming and immunotherapy response.NATURE CANCER,4(9).

Mei, Yan,et al."Siglec-9 acts as an immune-checkpoint molecule on macrophages in glioblastoma, restricting T-cell priming and immunotherapy response".NATURE CANCER 4.9(2023).