National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China; College of Biomedical Engineering, Sichuan University, Chengdu 610064, China; Medical School, Kunming University of Science and Technology, Kunming 650500, China.
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan University, Chengdu 610041, China.
Acta Biomater. 2023 Oct 15;170:427-441. doi: 10.1016/j.actbio.2023.08.046. Epub 2023 Aug 25.
Accumulating studies demonstrated that hydroxyapatite nanoparticles (HANPs) showed a selective anti-tumor effect, making them a good candidate for osteosarcoma (OS) treatment. However, the capacity of HANPs with different aspect ratios to regulate tumor immune microenvironment (TIM) was scarcely reported before. To explore it, the three HANPs with aspect ratios from 1.86 to 6.25 were prepared by wet chemical method. After a 24 or 72 h-exposure of OS UMR106 cells or macrophages to the nanoparticles, the tumor cells exhibited immunogenic cell death (ICD) indicated by the increased production of calreticulin (CRT), adenosine triphosphate (ATP) and high mobility group box 1 (HMGB1), and macrophages were activated with the release of pro-inflammatory cytokines. Next, the beneficial crosstalk between tumor cells and macrophages generated in the presence of HANPs for improved anti-tumor immunity activation. In the OS-bearing cognate rat model, HANPs inhibited OS growth, which was positively correlated with CRT and HMGB1 expression, and macrophage polarization in the tumor tissues. Additionally, HANPs promoted CD8 T cell infiltration into the tumor and systemic dendritic cell maturation. Particularly, HANPs bearing the highest aspect ratio exhibited the strongest immunomodulatory and anti-tumor function. This study suggested the potential of HANPs to be a safe and effective drug-free nanomaterial to control the TIM for OS therapy. STATEMENT OF SIGNIFICANCE: Emerging studies demonstrated that hydroxyapatite nanoparticles (HANPs) inhibited tumor cell proliferation and tumor growth. However, the underlying anti-tumor mechanism still remains unclear, and the capacity of HANPs without any other additive to regulate tumor immune microenvironment (TIM) was scarcely reported before. Herein, we demonstrated that HANPs, in an aspect ratio-dependent manner, showed the potential to delay the growth of osteosarcoma (OS) and to regulate TIM by promoting the invasion of CD8 T cells and F4/80 macrophages, and inducing immunogenic cell death (ICD) in tumors. This work revealed the new molecular mechanism for HANPs against OS, and suggested HANPs might be a novel ICD inducer for OS treatment.
越来越多的研究表明，羟基磷灰石纳米颗粒（HANPs）表现出选择性的抗肿瘤作用，使其成为骨肉瘤（OS）治疗的候选药物。然而，具有不同纵横比的 HANPs 调节肿瘤免疫微环境（TIM）的能力以前鲜有报道。为了探索这一点，通过湿法化学法制备了纵横比分别为 1.86 至 6.25 的三种 HANPs。将 UMR106 骨肉瘤细胞或巨噬细胞在纳米颗粒中暴露 24 或 72 小时后，肿瘤细胞表现出免疫原性细胞死亡（ICD），表现为钙网蛋白（CRT）、三磷酸腺苷（ATP）和高迁移率族蛋白 1（HMGB1）的增加产生，巨噬细胞通过释放前炎症细胞因子而被激活。接下来，在存在 HANPs 的情况下，肿瘤细胞和巨噬细胞之间产生有益的串扰，以改善抗肿瘤免疫激活。在骨肉瘤同源大鼠模型中，HANPs 抑制骨肉瘤生长，这与 CRT 和 HMGB1 的表达以及肿瘤组织中巨噬细胞的极化呈正相关。此外，HANPs 促进 CD8 T 细胞浸润肿瘤和系统树突状细胞成熟。特别是，具有最高纵横比的 HANPs 表现出最强的免疫调节和抗肿瘤功能。这项研究表明，HANPs 作为一种安全有效的无药物纳米材料具有控制 TIM 的潜力，可用于骨肉瘤治疗。
