Chen Kaiting, Li Xiaochen, Dong Shuyi, Guo Yu, Luo Ziyin, Zhuang Shi-Min, Liu Jie, Liu Tianrun, Liao Jing, Wen Weiping
Department of General Surgery of Otorhinolaryngology Head and Neck, The Sixth Affiliated Hospital, Sun Yat-Sen University, No.26, Erheng Road, Yuancun, Tianhe District, Guangzhou, 510655, China.
Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, No.26, Erheng Road, Yuancun, Tianhe District, Guangzhou, 510655, China.
J Transl Med. 2025 Jan 8;23(1):27. doi: 10.1186/s12967-024-06036-3.
Tumor-associated macrophages (TAMs) are pivotal immune cells within the tumor microenvironment (TME), exhibiting dual roles across various cancer types. Depending on the context, TAMs can either suppress tumor progression and weaken drug sensitivity or facilitate tumor growth and drive therapeutic resistance. This study explores whether targeting TAMs can suppress the progression of head and neck squamous cell carcinoma (HNSCC) and improve the efficacy of chemotherapy.
Bioinformatics analyses were performed to evaluate TAMs infiltration levels in HNSCC tumor tissues and examine their associations with patients' clinicopathological characteristics and prognosis. Flow cytometry was utilized to measure the expression of key macrophage markers and assess apoptosis following treatment with colony stimulating factor 1 receptor (CSF1R) inhibitors (BLZ945, PLX3397). Additionally, immunohistochemistry was employed to detect CD68 and CD8 expression. In vivo, the antitumor efficacy of CSF1R inhibitors was tested in mouse HNSCC tumor model, both as monotherapy and in combination with cisplatin, to evaluate potential synergistic effects.
Bioinformatic analysis identified TAMs as the predominant infiltrating immune cells in the TME of HNSCC, with significantly higher infiltration levels in tumor tissues compared to adjacent non-tumor tissues. High TAMs infiltration was associated with poorer overall survival (OS), disease-free survival (DFS), human papillomavirus (HPV) infection status, and advanced disease stages. The TAMs-related genes prediction model demonstrated high prognostic accuracy. CSF1R is primarily expressed in TAMs, where high CSF1R expression may suppress antigen binding and activation. In vitro experiments showed that CSF1R inhibitors induce TAMs apoptosis, enhance their phagocytic activity, and reduce CD206 expression and IL-10 secretion, thereby diminishing their immunosuppressive function. In vivo experiments revealed that while CSF1R inhibitors alone had limited efficacy in suppressing tumor growth, their combination with cisplatin significantly enhanced therapeutic efficacy, as evidenced by increased CD8 T cells infiltration within the TME.
Targeting TAMs via CSF1R inhibition enhances the therapeutic efficacy of cisplatin in HNSCC. These findings suggest that CSF1R inhibitors hold promise as a component of combination therapy for HNSCC.
肿瘤相关巨噬细胞（TAM）是肿瘤微环境（TME）中的关键免疫细胞，在多种癌症类型中发挥双重作用。根据具体情况，TAM既可以抑制肿瘤进展并削弱药物敏感性，也可以促进肿瘤生长并导致治疗耐药。本研究探讨靶向TAM是否可以抑制头颈部鳞状细胞癌（HNSCC）的进展并提高化疗疗效。
进行生物信息学分析以评估HNSCC肿瘤组织中TAM的浸润水平，并检查它们与患者临床病理特征和预后的关联。利用流式细胞术测量关键巨噬细胞标志物的表达，并评估集落刺激因子1受体（CSF1R）抑制剂（BLZ945、PLX3397）处理后的细胞凋亡情况。此外，采用免疫组织化学检测CD68和CD8的表达。在体内，在小鼠HNSCC肿瘤模型中测试CSF1R抑制剂作为单一疗法以及与顺铂联合使用时的抗肿瘤疗效，以评估潜在的协同作用。
生物信息学分析确定TAM是HNSCC的TME中主要的浸润免疫细胞，与相邻非肿瘤组织相比，肿瘤组织中的浸润水平显著更高。高TAM浸润与较差的总生存期（OS）、无病生存期（DFS）、人乳头瘤病毒（HPV）感染状态和晚期疾病阶段相关。TAM相关基因预测模型显示出较高的预后准确性。CSF1R主要在TAM中表达，高CSF1R表达可能抑制抗原结合和激活。体外实验表明，CSF1R抑制剂可诱导TAM凋亡，增强其吞噬活性，并降低CD206表达和IL-10分泌，从而削弱其免疫抑制功能。体内实验表明，虽然CSF1R抑制剂单独抑制肿瘤生长的效果有限，但它们与顺铂联合使用可显著提高治疗效果，TME内CD8 T细胞浸润增加证明了这一点。
通过抑制CSF1R靶向TAM可提高顺铂对HNSCC的治疗效果。这些发现表明，CSF1R抑制剂有望成为HNSCC联合治疗的组成部分。
