Mei, Wang, and Zhang et al. performed scRNAseq and spatial transcriptomics on neoadjuvant anti-PD-1-treated GBM patient samples, and identified a unique monocyte-derived macrophage subpopulation with high SIGLEC9 gene expression in the non-responders. Siglece deletion (murine homolog) increased immune cell infiltration and macrophage and T cell activation, restrained tumor growth, prolonged survival, and enhanced the efficacy of anti-PD-1/PD-L1 therapy in GBM mouse models. Siglece deletion activated CD4+ T cells and CD8+ T cells through antigen presentation, secreted chemokines, co-stimulatory factor interaction, and IFNγ-related pathway activation.
Contributed by Shishir Pant
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.
Author Info: (1) GMU-GIBH Joint School of Life Sciences, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou, China.
Author Info: (1) GMU-GIBH Joint School of Life Sciences, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou, China. Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China. (2) Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. (3) Department of Neurosurgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. (4) Cancer Institute, Xuzhou Medical University, Xuzhou, China. Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China. Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, China. (5) GMU-GIBH Joint School of Life Sciences, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou, China. Cancer Institute, Xuzhou Medical University, Xuzhou, China. Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, China. (6) Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. (7) GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, China. (8) Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. (9) Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. (10) Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. (11) Changping Laboratory, Beijing, China. (12) The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. (13) State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, China. (14) Department of Biology, Southern University of Science and Technology, Shenzhen, China. (15) Department of Neurosurgery, General Hospital of Southern Theater Command, Guangzhou, China. (16) Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. (17) Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. (18) Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. (19) GMU-GIBH Joint School of Life Sciences, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou, China. (20) Changping Laboratory, Beijing, China. (21) GMU-GIBH Joint School of Life Sciences, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou, China. (22) GMU-GIBH Joint School of Life Sciences, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou, China. (23) Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China. zhangqingling@gdph.org.cn. (24) GMU-GIBH Joint School of Life Sciences, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou, China. qbleng@gzhmu.edu.cn. (25) Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. chenjun23@mail.sysu.edu.cn. Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. chenjun23@mail.sysu.edu.cn. Key Laboratory of Tropical Disease Control of the Ministry of Education, Sun Yat-sen University, Guangzhou, China. chenjun23@mail.sysu.edu.cn. Jinfeng Laboratory, Chongqing, China. chenjun23@mail.sysu.edu.cn. (26) GMU-GIBH Joint School of Life Sciences, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou, China. guangshuaijia@icloud.com. Cancer Institute, Xuzhou Medical University, Xuzhou, China. guangshuaijia@icloud.com. Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, China. guangshuaijia@icloud.com.
