Siglec15, also known as sialic acid-binding immunoglobulin-like lectin 15, is an emerging immune checkpoint protein. It has a unique molecular composition and is highly prevalent in numerous solid tumor tissues and tumor-associated macrophages (TAMs) [2]. Siglec15 is implicated in osteoclast differentiation and bone remodeling, and can promote tumor development by repressing T lymphocyte activation and proliferation, facilitating tumor cell immune escape [2].

In bladder cancer, overexpression of Siglec15 led to a reduction in CD8+ T cell infiltration, mediated by down-regulation of pro-inflammatory cytokines and chemokines, exacerbating malignancy [6]. In breast cancer, osteoclast-derived apoptotic bodies inhibit naive CD8+ T cell activation via Siglec15, promoting secondary metastasis, and treatment with Siglec15 neutralizing antibodies reduces secondary metastases [1]. In anaplastic thyroid cancer, anti-Siglec15 antibody treatment increased the cytotoxic ability of CD8+ T cells, inhibited tumor growth, and prolonged mouse survival [3]. In pancreatic cancer, Siglec15+ TAM presents an M2-like phenotype, accelerating tumor growth and facilitating an immunosuppressive microenvironment [4]. In hepatocellular carcinoma, Siglec15 promotes immune evasion by inducing CD8+ T cell apoptosis [5]. In non-small cell lung cancer, Siglec15 knockdown inhibited cell proliferation, migration, and invasion, and down-regulation of Siglec15 in tumor cells enhanced the antitumor immune responses of CD8+ T cells [7].

In conclusion, Siglec15 plays a significant role in promoting tumor development and immune evasion in various cancers, mainly through inhibiting T cell-related immune responses. Studies using in vivo models such as mouse models have revealed its role in specific disease conditions, highlighting Siglec15 as a potential therapeutic target for cancer immunotherapy.

References:

1. Wu, Yutong, Ai, Hongbo, Xi, Yuhang, Luo, Fei, Dou, Ce. 2023. Osteoclast-derived apoptotic bodies inhibit naive CD8+ T cell activation via Siglec15, promoting breast cancer secondary metastasis. In Cell reports. Medicine, 4, 101165. doi:10.1016/j.xcrm.2023.101165. https://pubmed.ncbi.nlm.nih.gov/37607544/

2. Fan, Yujia, Sun, Liangliang, He, Juan, Ma, Hongli, Ding, Haitao. 2024. Siglec15 in blood system diseases: from bench to bedside. In Frontiers in immunology, 15, 1490505. doi:10.3389/fimmu.2024.1490505. https://pubmed.ncbi.nlm.nih.gov/39697338/

3. Bao, Lisha, Li, Ying, Hu, Xiaoping, Ge, Minghua, Pan, Zongfu. 2024. Targeting SIGLEC15 as an emerging immunotherapy for anaplastic thyroid cancer. In International immunopharmacology, 133, 112102. doi:10.1016/j.intimp.2024.112102. https://pubmed.ncbi.nlm.nih.gov/38652971/

4. Li, Tian-Jiao, Jin, Kai-Zhou, Li, Hao, Yu, Xian-Jun, Wu, Wei-Ding. 2022. SIGLEC15 amplifies immunosuppressive properties of tumor-associated macrophages in pancreatic cancer. In Cancer letters, 530, 142-155. doi:10.1016/j.canlet.2022.01.026. https://pubmed.ncbi.nlm.nih.gov/35077803/

5. Chen, Zheng, Yu, Mincheng, Zhang, Bo, Li, Hui, Guo, Lei. 2024. SIGLEC15, negatively correlated with PD-L1 in HCC, could induce CD8+ T cell apoptosis to promote immune evasion. In Oncoimmunology, 13, 2376264. doi:10.1080/2162402X.2024.2376264. https://pubmed.ncbi.nlm.nih.gov/38988824/

6. Deng, Dingshan, Xiao, Jiatong, Liu, Jinhui, Hu, Jiao, Zu, Xiongbing. 2024. Evasion of immunosurveillance by the upregulation of Siglec15 in bladder cancer. In Journal of hematology & oncology, 17, 117. doi:10.1186/s13045-024-01638-2. https://pubmed.ncbi.nlm.nih.gov/39609852/

7. Liang, Haifeng, Chen, Qing, Hu, Zhichao, Jiang, Libo, Dong, Jian. . Siglec15 facilitates the progression of non-small cell lung cancer and is correlated with spinal metastasis. In Annals of translational medicine, 10, 281. doi:10.21037/atm-22-764. https://pubmed.ncbi.nlm.nih.gov/35434017/