Siglecs, Novel Immunotherapy Targets, Potentially Enhance The Effectiveness of Existing Immune Checkpoint Inhibitors in Glioma Immunotherapy

Guan-Zhang Li,1,* Ke-Nan Zhang,1,* Zheng Wang,2 Hui-Min Hu,1 Zhi-Liang Wang,1 Ruo-Yu Huang,1 Hao-Yu Jiang,2 You Zhai,1 Yue-Mei Feng,1 Yuan-Hao Chang,1 Ren-Peng Li,2 Fan Wu,1 Fan Zeng,1 Tao Jiang,1–4 Wei Zhang2 1Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, People’s Republic of China; 2Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, People’s Republic of China; 3Center of Brain Tumor, Beijing Institute for Brain Disorders, Beijing 100070, People’s Republic of China; 4China National Clinical Research Center for Neurological Diseases, Beijing 100070, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei Zhang; Tao JiangDepartment of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, No. 119 South Fourth Ring Road West, Fengtai District, Beijing, People’s Republic of ChinaTel +86 180 1021 2611Email zhangwei_vincent@126.com; taojiang1964@163.comBackground: Inhibitors of immune checkpoints have shown little effect in clinical trials involving glioma patients. Here, we explored novel targets for use in future treatments. Previous studies showed the sialic acid-binding Ig-like lectin (Siglec) family to have a specific role in immunosuppression. We aimed to study the characteristics and immune function of Siglec family members.Methods: Transcriptome data from 1024 glioma samples and 1551 glioma single cells were used in our study. Clinical and molecular pathology information was also included. Statistical, bioinformatical methods, and single-cell sequencing analysis were applied to investigate the role of Siglec family members.Results: Siglecs-5, −7, −9, and −16 showed a significant correlation with immunosuppression in glioma. They are typically expressed in higher grade, IDH-wildtype, and mesenchymal subtype gliomas. Siglec-5, −7, and −9 had a similar immune function to TIM-3, while Siglec-16 was similar to PD-L1, suppressing tumor immunity via different mechanisms. Joint use of Siglec-inhibitors and immune checkpoint inhibitors could prolong the survival of glioma patients.Conclusion: Siglec-5, −7, −9, and −16 suppressed tumor immunity in different ways. Joint usage of inhibitors may be an effective means to improve the efficacy of glioma immunotherapy.Keywords: glioma, Siglec family, immunotherapy, single-cell sequencing analysis, prognosis