Hu Minwan, Tang Borui, Zhang Di, Wang Xuhong, Zhao Xiuli
Department of Clinical Pharmacology, Affiliated Beijing Luhe Hospital of Capital Medical University, Beijing 101149, PR China; School of Pharmaceutical Sciences, Capital Medical University, Beijing, PR China; Department of National Institute for Drug Clinical Trial, Affiliated Beijing Tongren Hospital of Capital Medical University, Beijing 100005, PR China.
School of Pharmaceutical Sciences, Capital Medical University, Beijing, PR China; Department of National Institute for Drug Clinical Trial, Affiliated Beijing Tongren Hospital of Capital Medical University, Beijing 100005, PR China.
Int Immunopharmacol. 2025 Feb 6;147:114005. doi: 10.1016/j.intimp.2024.114005. Epub 2025 Jan 7.
CD276 has been identified as a novel immune checkpoint, and its overexpression is associated with immune evasion and poor prognosis in various tumors, including head and neck squamous cell carcinoma (HNSCC). Nimotuzumab, a humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody, has been approved for various solid tumors. However, it remains unclear whether its anticancer efficacy involves a reduction in CD276 expression. The purpose of this study was to investigate the regulatory effects and potential mechanisms of nimotuzumab on CD276 expression both in vitro and in vivo. In a coculture system, nimotuzumab showed inhibitory effects on TGF-β-induced upregulation of CD276 at both the transcriptional and protein levels in HNSCC cell lines. Mechanistic studies revealed that nimotuzumab primarily suppressed TGF-β-induced CD276 upregulation by blocking EGFR/MEK/ERK, which was further validated by MEK and ERK inhibitors. In xenograft and mice HNSCC models, nimotuzumab exerted antitumor effects accompanied by significantly reduced CD276 expression during tumor progression. Analysis of tumor-infiltrating lymphocytes (TILs) profiles indicated that nimotuzumab orchestrated the tumor immune microenvironment (TIME) by notably increasing the frequency of T lymphocytes, including cytotoxic T lymphocytes and helper T lymphocytes, as well as macrophage cells. However, no significant changes were observed in the populations of NK cells, DC cells, and neutrophils. These findings offer new insights into the anticancer mechanisms of nimotuzumab and its underlying synergy in combined treatments with immunotherapy for HNSCC.
CD276已被确定为一种新型免疫检查点，其过表达与包括头颈部鳞状细胞癌（HNSCC）在内的多种肿瘤的免疫逃逸和不良预后相关。尼妥珠单抗是一种人源化抗表皮生长因子受体（EGFR）单克隆抗体，已被批准用于多种实体瘤。然而，其抗癌疗效是否涉及CD276表达的降低仍不清楚。本研究的目的是在体外和体内研究尼妥珠单抗对CD276表达的调节作用及其潜在机制。在共培养系统中，尼妥珠单抗在转录和蛋白水平上均对HNSCC细胞系中转化生长因子-β（TGF-β）诱导的CD276上调具有抑制作用。机制研究表明，尼妥珠单抗主要通过阻断EGFR/MEK/ERK来抑制TGF-β诱导的CD276上调，MEK和ERK抑制剂进一步验证了这一点。在异种移植和小鼠HNSCC模型中，尼妥珠单抗发挥抗肿瘤作用，同时在肿瘤进展过程中CD276表达显著降低。肿瘤浸润淋巴细胞（TILs）谱分析表明，尼妥珠单抗通过显著增加T淋巴细胞（包括细胞毒性T淋巴细胞和辅助性T淋巴细胞）以及巨噬细胞的频率来调控肿瘤免疫微环境（TIME）。然而，自然杀伤细胞、树突状细胞和中性粒细胞的数量未观察到显著变化。这些发现为尼妥珠单抗的抗癌机制及其在HNSCC免疫治疗联合治疗中的潜在协同作用提供了新的见解。
