Siglec15, a sialic acid-binding immunoglobulin-like lectin, has emerged as a significant molecule in the immune-tumor interaction landscape. It is involved in immune evasion mechanisms, mainly by suppressing T lymphocyte activation and proliferation, and is also implicated in osteoclast differentiation and bone remodeling [2]. In the tumor microenvironment (TME), it can shape a non-inflamed state, influencing cancer progression and response to immunotherapy.

In bladder cancer, overexpression of Siglec15 leads to reduced CD8+ T cell infiltration by downregulating pro-inflammatory cytokines and chemokines, exacerbating malignancy and contributing to immune evasion [6]. In breast cancer, osteoclast-derived apoptotic bodies inhibit naive CD8+ T cell activation via Siglec15, promoting secondary metastasis [1]. In anaplastic thyroid cancer, blocking Siglec15 with an antibody increases the cytotoxic ability of CD8+ T cells, inhibits tumor growth, and prolongs mouse survival [3]. In pancreatic cancer, Siglec15+ tumor-associated macrophages (TAMs) present an M2-like phenotype, accelerating tumor growth and 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 inhibits cell proliferation, migration, and invasion, and down-regulation of Siglec15 in tumor cells enhances the antitumor immune responses of CD8+ T cells [7].

In conclusion, Siglec15 plays a crucial role in immune evasion and tumor progression across multiple cancer types. Mouse models, especially those involving gene knockout (KO) or conditional knockout (CKO) of Siglec15, have been instrumental in revealing its functions in specific disease conditions, highlighting its potential as a 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/