Beijing Institute of Dental Research, Beijing Stomatological Hospital and School of Stomatology, Capital Medical University, No.4 Tiantanxili, Dongcheng District, Beijing 100050, China.
Beijing Institute of Dental Research, Beijing Stomatological Hospital and School of Stomatology, Capital Medical University, No.4 Tiantanxili, Dongcheng District, Beijing 100050, China; Department of Stomatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.
Arch Oral Biol. 2024 Oct;166:106043. doi: 10.1016/j.archoralbio.2024.106043. Epub 2024 Jul 3.
Combing PD-1/PD-L1 immune checkpoint inhibitors with natural products has exhibited better efficacy than monotherapy. Hence, the purpose of this research was to examine the anti-cancer effects of brusatol, a natural quassinoid-terpenoid derived from Brucea javanica, when used in conjunction with an anti-mouse-PD-1 antibody in a murine head and neck squamous cell carcinoma (HNSCC) model and elucidate underlying mechanisms.
A murine HNSCC model and an SCC-15 cell xenograft nude mouse model were established to investigate the anti-cancer effects of brusatol and anti-PD-1 antibody. Mechanistic studies were performed using immunohistochemistry. Cell proliferation, migration, colony formation, and invasion were evaluated by MTT, migration, colony formation, and transwell invasion assays. PD-L1 levels in oral squamous cell carcinoma (OSCC) cells were assessed through qRT-PCR, flow cytometry, and western blotting assays. The impact of brusatol on Jurkat T cell function was assessed by an OSCC/Jurkat co-culture assay.
Brusatol improved tumor suppression by anti-PD-1 antibody in HNSCC mouse models. Mechanistic studies revealed brusatol inhibited tumor cell growth and angiogenesis, induced apoptosis, increased T lymphocyte infiltration, and reduced PD-L1 expression in tumors. Furthermore, in vitro assays confirmed brusatol inhibited PD-L1 expression in OSCC cells and suppressed cell migration, colony formation, and invasion. Co-culture assays indicated that brusatol's PD-L1 inhibition enhanced Jurkat T cell-mediated OSCC cell death and reversed the inhibitory effect induced by OSCC cells.
Brusatol improves anti-PD-1 antibody efficacy by targeting PD-L1, suggesting its potential as an adjuvant in anti-PD-1 immunotherapy.
将 PD-1/PD-L1 免疫检查点抑制剂与天然产物联合使用比单药治疗显示出更好的疗效。因此，本研究旨在研究布瑞佐菌素（一种源自苦木的天然喹诺酮萜烯）与抗小鼠 PD-1 抗体联合使用在小鼠头颈部鳞状细胞癌（HNSCC）模型中的抗癌作用，并阐明其潜在机制。
建立了小鼠 HNSCC 模型和 SCC-15 细胞异种移植裸鼠模型，以研究布瑞佐菌素和抗 PD-1 抗体的抗癌作用。使用免疫组织化学进行机制研究。通过 MTT、迁移、集落形成和 Transwell 侵袭试验评估细胞增殖、迁移、集落形成和侵袭。通过 qRT-PCR、流式细胞术和 Western blot 分析评估口腔鳞状细胞癌（OSCC）细胞中的 PD-L1 水平。通过 OSCC/Jurkat 共培养测定评估布瑞佐菌素对 Jurkat T 细胞功能的影响。
布瑞佐菌素改善了 HNSCC 小鼠模型中抗 PD-1 抗体的肿瘤抑制作用。机制研究表明，布瑞佐菌素抑制肿瘤细胞生长和血管生成，诱导细胞凋亡，增加 T 淋巴细胞浸润，并降低肿瘤中的 PD-L1 表达。此外，体外试验证实布瑞佐菌素抑制 OSCC 细胞中的 PD-L1 表达，并抑制细胞迁移、集落形成和侵袭。共培养测定表明，布瑞佐菌素抑制 PD-L1 增强 Jurkat T 细胞介导的 OSCC 细胞死亡，并逆转 OSCC 细胞诱导的抑制作用。
布瑞佐菌素通过靶向 PD-L1 提高抗 PD-1 抗体的疗效，表明其在抗 PD-1 免疫治疗中具有潜在应用价值。
